CN101133026A - 1- sulfonyl-pi perdine- 3 -carboxyl i c acid amide derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase for the treatment of type ii diabetes mellitus - Google Patents
1- sulfonyl-pi perdine- 3 -carboxyl i c acid amide derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase for the treatment of type ii diabetes mellitus Download PDFInfo
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- CN101133026A CN101133026A CNA2006800067895A CN200680006789A CN101133026A CN 101133026 A CN101133026 A CN 101133026A CN A2006800067895 A CNA2006800067895 A CN A2006800067895A CN 200680006789 A CN200680006789 A CN 200680006789A CN 101133026 A CN101133026 A CN 101133026A
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- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
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- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Abstract
Provided herein are compounds of the formula (I) as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, type II diabetes mellitus and metabolic syndrome.
Description
The present invention relates to the 11beta-Hydroxysteroid dehydrogenase inhibitor of formula as described below (I).This inhibitor comprises for example arylsulfonyl phenylpiperidines, and can be used for the treatment of disease such as type ii diabetes and metabolism syndrome.The invention still further relates to the pharmaceutical composition of the 11beta-Hydroxysteroid dehydrogenase that comprises formula as described below (I).The file that following institute quotes or relies on all is combined in this clearly by reference.
Diabetes are a kind of serious diseases, and it influences the increasing people of whole world quantity.Its incidence and many national obesity ascendant trends progressively rise abreast.The serious consequence of diabetes comprises that apoplexy, heart trouble, injury of the kidney, danger blind and surgical blanking increase.
Diabetes are characterised in that the insulin secretion of minimizing and/or peripheral tissues are impaired to the responding ability of Regular Insulin, cause the plasma glucose levels that increases.The diabetes that have two kinds of forms: insulin-dependent and non-insulin-depending type, wherein most diabetes suffer the non-insulin-depending type form of this disease, are called type ii diabetes or non insulin dependent diabetes (NIDDM).Because its serious consequence presses for control of diabetes.
The treatment of NIDDM is usually from loss of weight, health diet and exercise plan.These factors are particularly importants for the cardiovascular danger aspect that solves the increase relevant with diabetes, but they are invalid for control disease itself usually.There is utilizable multiple pharmacological agent, comprises Regular Insulin, N1,N1-Dimethylbiguanide, sulfonylurea, acarbose and thiazolidinediones.But each in these treatments all has shortcoming, the current newtype drug that needs the treatment diabetes.
N1,N1-Dimethylbiguanide is the beneficial agents that reduces fasting blood glucose level and increase the insulin sensitivity of peripheral tissues.N1,N1-Dimethylbiguanide has many effects in vivo, comprises that glycogen (storing the polymerized form of glucose) synthetic improves [R.A.De Fronzo, Drugs 1999,58 Suppl.1,29].N1,N1-Dimethylbiguanide also has useful effect for lipid profile, has the reduction [S.E.Inzucchi JAMA2002,287,360] that the effective result-treatment of employing N1,N1-Dimethylbiguanide causes the level of LDL cholesterol and tri-glyceride for cardiovascular health.Yet after for many years, N1,N1-Dimethylbiguanide is lost its effectiveness JAMA 1999,281,2005 such as [] R.C.Turner, therefore needs the new treatment of diabetes.
Thiazolidinediones is the activator of the peroxisome proliferator-activated property of nuclear receptor receptor-gamma.Their effective lowering blood glucose levels, their effect are mainly owing to the insulin resistance [M.Tadayyon and S.A.Smith Expert Opin.Investig.Drugs 2003,12,307] that reduces in the skeletal muscle.A shortcoming relevant with using thiazolidinediones is weightening finish.
Sulfonylurea receptors bind on sulfonylurea and the pancreatic beta cell stimulates insulin secretion, thus the lowering blood glucose level.Weightening finish [S.E.Inzucchi JAMA 2002,287,360] is also followed in the use of sulfonylurea, and similar N1,N1-Dimethylbiguanide, and they in time and [R.C.Turner etc., JAMA 1999,281,2005] are renderd a service in forfeiture.Another problem that often runs in the patient with sulfonylurea treatment is hypoglycemia [M.Salas J.J. and Caro Adv.Drug React.Tox.Rev.2002,21,205-217].
Acarbose is the inhibitor of enzyme alpha-glucosidase, alpha-glucosidase degrade in intestines disaccharides and compounding sugar.It has than N1,N1-Dimethylbiguanide or the lower effect of sulfonylurea, and it causes intestines not accommodate diarrhoea, and these often cause stopping using acarbose [S.E.Inzucchi JAMA 2002,287,360]
Because do not have a kind of permanently effectively and do not have a severe side effect in these treatments, therefore need the newtype drug of treatment type ii diabetes.
Metabolism syndrome demonstrates illness more than two kinds following symptom for patient wherein: obesity, hypertriglyceridemia, low-level HDL-cholesterol, the fasting blood glucose level of hypertension and rising.This syndrome is the omen of type ii diabetes normally, and has 24% height in the U.S. and estimate sickness rate (E.S.Ford etc., JAMA 2002,287,356).The therapeutical agent that improves metabolism syndrome can be used to reduce or stop the progress of type ii diabetes.
In liver, produce glucose by two kinds of diverse ways: glyconeogenesis, wherein separate by producing new glucose and sugar with a series of enzymic catalytic reaction with pyruvate salt, wherein the decomposition by the polymkeric substance glycogen produces glucose.
Two kinds of key enzymes in the glyconeogenesis method are catalysis oxosuccinic acids to the hydrolysis of the phosphoenolpyruvate carboxykinase (PEPCK) of the conversion of phosphoenolpyruvic acid and catalysis G-6-P to obtain the G-6-Pase (G6Pase) of free glucose.By the catalytic oxosuccinic acid of PEPCK to the conversion of phosphoenolpyruvic acid is the rate limiting step in glyconeogenesis.On an empty stomach,, thereby can improve the speed of glyconeogenesis simultaneously to adjusted PEPCK and G6Pase.Be subjected to the control (philtrum is a hydrocortisone, and is Kendall compound in the mouse) of corticosteroid hormone the horizontal component of these enzymes.When reflunomide is attached to the reflunomide acceptor, triggering signal series connection, cause these enzymes to adjusted.
Find the 11-dehydrogenation counterpart (being respectively cortisone and 11-dehydrocorticosterone in people and mouse) of corticosteroid hormone and their oxidations in vivo, they do not have activity at the glycocorticosteroid receptor place.The partial concn in the tissue of expressing the reflunomide acceptor is depended in these functionss of hormones.This partial concn can be different from the cyclical level of hormone in blood plasma, and reason is the effect of oxydo-reductase in tissue.The enzyme of modifying the hormone state of oxidation is the 11beta-Hydroxysteroid dehydrogenase of I type and II type.I type (11 β-HSD1) be responsible in vivo cortisone being reduced to hydrocortisone, and II type (11 β-HSD2) be responsible for hydrocortisone is oxidized to cortisone.These enzymes have low homology and express in different tissues.11 β-HSD1 expresses at the camber of organizing in a large number that comprises liver, fatty tissue and brain, and 11 β-HSD2 is in mineralocorticoid destination organization such as kidney and the expression of colon camber.11 β-HSD2 prevents that hydrocortisone is attached to the mineralocorticoid acceptor, and finds that the defective in this enzyme is relevant with apparent mineralocorticoid excessive (AME) syndrome.
Thereby since 11 beta-hydroxysteroids be attached to that the reflunomide acceptor causes PEPCK improve glucose level to adjusted, therefore suppressing 11 β-HSD1 is the approach that is hopeful of treatment diabetes.Except top biological chemistry is discussed, also have evidence, and from people's small clinical studies, this treatment potentiality that suppress 11 β-HSD1 have been proved from transgenic mice.
Adopt experiment showed, that 11 β-HSD1 is active and being adjusted in the diabetes and in metabolism syndrome, can having useful result of treatment of transgenic mice.For example, when in mouse, knocking out 11 β-HSD1 gene, do not cause the normal raising of G6Pase and PEPCK level on an empty stomach, and animal to stress-or fat relevant hyperglycemia is insensitive.And, make its control animal have significantly low fasting glucose level (Y.Kotolevtsev etc., Proc.Natl.Acad.Sci.USA 1997,94,14924) to the knock-out animal weight/power ratio of high fat diet obesity coupling.Find that also 11 β-HSD1 knock-out mice has the lipid profile of raising, insulin sensitivity and glucose tolerance (N.M.Morton etc., J.Biol.Chem.2001,276,41293).Also studied the effect of overexpression 11 β in mouse-HSD1 gene.These transgenic mices demonstrate the 11 β-HSD1 activity of raising in fatty tissue, and they also demonstrate the internal organ obesity relevant with metabolism syndrome.The Kendall compound level raises in fatty tissue, and does not raise in serum, and mouse has the fat level of rising, especially when high fat diet.The mouse of feed low fat diet be hyperglycemia with hyperinsulinar, and show glucose intolerance and insulin resistance (H.Masuzaki etc., Science, 2001,294,2166).
Studied the effect of non-selective 11beta-Hydroxysteroid dehydrogenase inhibitor carbenoxolone with a large amount of small tests for the people.In a research, find that carbenoxolone causes whole health insulin sensitivity to improve, and this raising helps to reduce hepatic glucose production (B.R.Walker etc., J.Clin.Endocrinol.Metab.1995,80,3155).In another research, in diabetic but observe the glucose production of reduction and the glycogenolysis (R.C.Andrews etc., J.Clin.Enocrinol.Metab.2003,88,285) of response glucagon challenge among the unsound experimenter.At last, find that carbenoxolone improves healthy geriatric man and type ii diabetes people's cognitive function (T.C.Sandeep etc., Proc.Natl.Acad.Sci USA 2004,101,6734).
Determine a large amount of nonspecific inhibitors of 11 β-HSD1 and 11 β-HSD2, comprise glycyrrhetinic acid, sylvic acid and carbenoxolone.In addition, found a large amount of selective depressants of 11 β-HSD1, comprise Chenodiol, flavanone and 2 '-hydroxyl flavanone (S.Diederich etc., Eur.J.Endocrinol.2000,142,200 and R.A.S.Schweizer etc., Mol.Cell.Endocrinol.2003,212,41).
WO 2004089470, WO 2004089416 and WO 2004089415 (Novo NordiskA/S) disclose the compound with a large amount of different types of structure as the 11bHSD1 inhibitor, and this compound can be used for the treatment of metabolism syndrome and relevant disease and illness.
WO 0190090, WO 0190091, WO 0190092, WO 0190093, WO 03043999 (Biovitrum AB) disclose the compound as 11 beta-HSD 1 inhibitors.The structure of these compounds is different from the structure of The compounds of this invention.WO 2004112781 and WO 2004112782 disclose in these compounds some have been used to promote the method for wound healing.
WO 0190094, WO 03044000, WO 03044009 and WO 2004103980 (Biovitrum AB) disclose the compound as 11 beta-HSD 1 inhibitors.The structure of these compounds is different from the structure of The compounds of this invention.WO 2004112785 discloses in these compounds some has been used to promote the method for wound healing.
WO 03065983, WO 03075660, WO 03104208, WO 03104207, US20040133011, WO 2004058741 and WO 2004106294 (Merck﹠amp; Co., Inc.) compound as 11 beta-HSD 1 inhibitors disclosed.The structure of these compounds is different from the structure of The compounds of this invention.US2004122033 discloses the combination of appetite-inhibiting agent and 11 beta-HSD 1 inhibitors, and it is used for the treatment of fat with fat relevant illness.
WO 2004065351 (Novartis); WO 2004056744 and WO 2004056745 (Janssen Pharmaceutica N.V.); Compound as 11 beta-HSD 1 inhibitors is disclosed with WO 2004089367 and WO 2004089380 (NovoNordisk A/S).The structure of these compounds is different from the structure of The compounds of this invention.
WO 2004089415 (Novo Nordisk A/S) discloses the application of 11 beta-HSD 1 inhibitors and the combination of glucocorticoid receptor excitomotor, is used for the treatment of disease, comprises cancer and the disease that relates to inflammation.Disclose several different types of 11 beta-HSD 1 inhibitors, comprised amino-ketone, benzimidazoles, carboxyl acylamide, 2,3-Dihydrobenzofuranes-7-carboxyl acylamide, indoles, methylenedioxyphenyl-carboxyl acylamide ， oxazole-4-carboxyl acylamide oxazole-5-carboxyl acylamide pyrazolo [1,5-a] miazines, pyrazole-4-carboxamide class, thiazole-4-carboxyl acylamide, thiazole-5-carboxyl acylamide and 1,2, the 4-triazole species.WO2004089416 (Novo Nordisk A/S) discloses the application of 11 beta-HSD 1 inhibitors and antihypertensive drug combination, is used for the treatment of disease and comprises insulin resistance, hyperlipemia and obesity.WO2004089470 (Novo Nordisk A/S) discloses the substituted amide class as 11 beta-HSD 1 inhibitors.
WO 2004089471 (Novo NordiskA/S) discloses pyrazolo [1, the 5-a] miazines as 11 beta-HSD 1 inhibitors; WO 2004089896 (Novo Nordisk A/S) discloses the compound as 11 beta-HSD 1 inhibitors; WO 2004037251A1 (Sterix Limited) discloses the sulfonamides as 11 beta-HSD 1 inhibitors; WO 2004027047A2 (HartmutHanauske-Abel) discloses the compound as 11 beta-HSD 1 inhibitors; Compound as 11 beta-HSD 1 inhibitors is disclosed with WO2004011410, WO 2004033427 and WO 2004041264 (AstraZeneca UK Limited).The structure of these compounds is different from the structure of The compounds of this invention.
The reagent of WO 02076435A2 (The University of Edinburgh) claimed reduction by 11 β-HSD1 level is used for promoting artery to protect the application of the composition of lipid profile (atheroprotectivelipid profile) in preparation.The reagent of mentioning as 11 beta-HSD 1 inhibitors comprises carbenoxolone, 11-oxo Progesterone, 3 α, 17,21-trihydroxy--5 β-pregnane-3-ketone, 21-hydroxyl-pregnant-4-alkene-3,11,20-triketone, hero-4-alkene-3,11,20-triketone and 3 beta-hydroxies androst-5-ene-17-ketone.These compounds do not have a kind of and similar The compounds of this invention.
WO 03059267 (Rhode Island Hospital) is claimed a kind ofly to treat the method for glucocorticosteroid correlation behavior, described inhibitor such as 11-ketone testosterone, 11-ketone-androsterone by administration 11 beta-HSD 1 inhibitors; 11-ketone-pregnenolone; 11-ketone-dehydrogenation-Biao Androstenedione, 3 α, 5 α-reduction-11-ketone Progesterone; 3 α; 5 α-reduction-11-ketone testosterone, 3 α, 5 α-reduction-11-ketone-Androstenedione; or 3 α, 5 α-tetrahydrochysene-11 β-dehydrogenation-Kendall compound.These compounds do not have a kind of and similar The compounds of this invention.
WO 9610022 (Zeneca Limited) discloses 1-[[1-(2-naphthyl the alkylsulfonyl)-3-piperidyl as antithrombotic agent or anti-coagulant] carbonyl]-4-(4-pyridyl)-piperazine.
WO 2004018428 (Pharmacia﹠amp; Upjohn) 5-cyano group-2-[[[4-[[3-[(diethylamino as antiseptic-germicide is disclosed) carbonyl]-piperidino] alkylsulfonyl]-5-methyl-2-thienyl] carbonyl] amino]-phenylformic acid.
WO 2004018414 (Pharmacia﹠amp; Upjohn) 5-cyano group-2-[[3-[[3-[(diethylamino as antiseptic-germicide is disclosed) carbonyl]-piperidino] alkylsulfonyl] benzoyl] amino]-phenylformic acid and 5-cyano group-2-[[4-[[3-[(diethylamino) carbonyl]-piperidino] alkylsulfonyl] benzoyl] amino]-phenylformic acid.
WO 2002020015 (Merck﹠amp; Co., Inc.) disclose in the macrocyclic hcv inhibitors of the prenyl protein transferase of preparation as the N-[(1R of intermediate)-1-(4-cyano group-3-fluorophenyl)-1-(1-methyl isophthalic acid H-imidazoles-5-yl) ethyl]-the 1-[(3-p-methoxy-phenyl) alkylsulfonyl]-3-piperidines carboxylic acid amides and N-[(1R)-1-(4-cyano group-3-fluorophenyl)-1-(1-methyl isophthalic acid H-imidazoles-5-yl) ethyl]-the 1-[(3-hydroxy phenyl) alkylsulfonyl]-3-piperidines carboxylic acid amides.
(Bayer, A.G. Germany) disclose compound as inflammatory, active immunity and Immunological diseases inhibitor to US 2004029883.The structure of these compounds is different from the structure of The compounds of this invention.
GB 2351733 and C.Zhou etc.; Bioorg.Med.Chem.Lett.2001; 11; 415 disclose (β the S)-N-[[1-[(4-fluorophenyl as somatostatin receptor 2 excitomotors) alkylsulfonyl]-the 3-piperidyl] carbonyl]-Beta-methyl-D-tryptophyl-L-Methionin; 1; 1-dimethyl ethyl ester, monoacetate, (β S)-N-[[1-[(3; the 4-Dimethoxyphenyl) alkylsulfonyl]-the 3-piperidyl] carbonyl]-Beta-methyl-D-tryptophyl-L-Methionin; 1,1-dimethyl ethyl ester and (β S)-Beta-methyl-N-[[1-(2-thienyl sulphonyl base)-3-piperidyl] carbonyl]-D-tryptophyl-L-Methionin, 1; 1-dimethyl ethyl ester; it is used for the treatment of and prevent diabetes, cancer, acromegaly; depressed; chronic atrophic gastritis, Crohn disease, ulcerative colitis; retinopathy; sacroiliitis, internal organ and nervosa be pain simultaneously, and prevent restenosis.The structure of these compounds is different from the structure of The compounds of this invention.
WO 2001012186 (Biogen Inc.) discloses (2S)-4-[[(2S)-4-methyl-2-[methyl as cell adhension inhibitors [[4-[[[(2-aminomethyl phenyl) amino] carbonyl] amino] phenyl] ethanoyl] amino]-1-oxo amyl group] amino]-2-[[[(3S)-and 1-(phenyl sulfonyl)-3-piperidyl] carbonyl] amino]-butyric acid.The structure of these compounds is different from the structure of The compounds of this invention.
WO 2001007440 (Boehringer Ingelheim Pharmaceuticlas; Inc.) 1-[[(3R as antiphlogiston is disclosed)-the 3-[(4-bromophenyl) methyl]-1-(3; the 5-dichlorophenyl)-2; 3-dihydro-3-methyl-2-oxo-1H-imidazo [1; 2-a] imidazoles-5-yl] alkylsulfonyl]-N, N-diethyl-3-piperidines carboxylic acid amides.
WO 2000048623 (Kaken Pharmaceutical Co.; Ltd) N-[(1R as tethelin is disclosed)-the 2-[(3-aminopropyl) amino]-1-(2-naphthyl methyl)-2-oxoethyl]-1-(phenyl sulfonyl)-3-piperidines carboxylic acid amides, a hydrochloride (9CI).
US 5,817,678 (Merck﹠amp; Co.; Inc.) (3S)-N-[2-[1-[(4-cyano-phenyl as inhibition of farnesyl protein transferase is disclosed) methyl]-1H-imidazoles-5-yl] ethyl]-1-(phenyl sulfonyl)-3-piperidines carboxylic acid amides; (3S)-and the N-[2-[1-[(4-cyano-phenyl) methyl]-1H-imidazoles-5-yl] ethyl]-1-(naphthalene sulfonyl base)-3-piperidines carboxylic acid amides; (3S)-and the 1-[(3-chloro-phenyl-) alkylsulfonyl]-the N-[2-[1-[(4-cyano-phenyl) methyl]-1H-imidazoles-5-yl] ethyl]-3-piperidines carboxylic acid amides; (3S)-and the N-[2-[1-[(4-cyano-phenyl) methyl]-1H-imidazoles-5-yl] ethyl]-1-[(3, the 5-dichlorophenyl) alkylsulfonyl]-3-piperidines carboxylic acid amides.
WO 9910523, WO 9910524, WO 9910525 and WO 2000016626 (Merck﹠amp; Co., Inc.) (3S)-N-[2-[1-[(4-cyano-phenyl as the prenyl protein transferase inhibitor used of treatment cancer is disclosed also) methyl]-1H-imidazoles-5-yl] ethyl]-1-[(3, the 5-dichlorophenyl) alkylsulfonyl]-3-piperidines carboxylic acid amides.
Scozzafava etc., Eur.J.Med.Chem.2000,35,31 disclose N-[2-(1H-imidazol-4 yl) ethyl as carbonic anhydrase isozyme I, II and IV activator]-the 1-[(4-aminomethyl phenyl) alkylsulfonyl]-3-piperidines carboxylic acid amides.
DE 19827640 (Bayer A.-G.) discloses 1-[[3-(the 7-cyclopentyl-1 as phosphodiesterase inhibitor; 4-dihydro-5-methyl-4-oxo-imidazole also [5; 1-f] [1; 2,4] triazine-2-yl)-and the 4-ethoxyl phenenyl] alkylsulfonyl]-N, N-diethyl-3-piperidines carboxylic acid amides; 1-[[3-(7-suberyl-1; 4-dihydro-5-methyl-4-oxo-imidazole is [5,1-f] [1,2 also; 4] triazine-2-yl)-and the 4-ethoxyl phenenyl] alkylsulfonyl]-N; N-diethyl-3-piperidines carboxylic acid amides and 1-[[4-oxyethyl group-3-(7-hexyl-1,4-dihydro-5-methyl-4-oxo-imidazole also [5; 1-f] [1; 2,4] phenyl triazine-2-yl)] alkylsulfonyl]-N, N-diethyl-3-piperidines carboxylic acid amides.
WO 9964004 (Bristol-Myers Squibb Company) discloses the 1-[[1-[[3-(5 as the cGMP phosphodiesterase inhibitor; 8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazoline-6-yl)-and 4-propoxy-phenyl] alkylsulfonyl]-the 3-piperidyl] carbonyl]-4-methyl-piperazine.
But in the art, for being used for the treatment of other 11 beta-HSD 1 inhibitors that disease such as type ii diabetes and metabolism syndrome have effect, existing needs.In addition, be lower than the 11 beta-HSD 1 inhibitors existence needs of about 1 μ M in the art for the IC50 value.
Should be appreciated that the technical terms that adopts is used to describe the purpose of specific embodiment herein, and do not think restrictive.In addition, although when enforcement and advance copy invention, can use and those any method, device or materials similar or of equal value of describing, preferable methods, device and material are described now herein.
In this manual, term " aryl " be used for expression single-or polycyclic aromatic ring system, wherein said ring can be that carbocyclic ring maybe can contain one or more and is selected from atom among O, S and the N.The example of aryl has: phenyl, pyridyl, benzimidazolyl-, benzofuryl, benzothiazolyl, benzothienyl, cinnolines base, furyl, imidazo [4,5-c] pyridyl, imidazolyl, indyl, isoquinolyl ， isoxazolyl, naphthyl, [1,7] phthalazinyl ， oxadiazole Ji ， oxazolyl, 2, the 3-phthalazinyl, purine radicals, pyridazinyl, pyrazolyl, pyrido [2,3-d] pyrimidyl, pyrimidyl, Mi Dingbing [3,2-c] pyrimidyl, pyrrolo-[2,3-d] pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl etc.
As used herein, term " alkyl " for example is meant, branching or nonbranched, and ring-type or acyclic, saturated or undersaturated (as alkenyl or alkynyl) alkyl, it can be replacement or unsubstituted.Under the cyclic situation, alkyl is preferably C
3To C
12, C more preferably
5To C
10, C more preferably
5To C
7Under acyclic situation, alkyl is preferably C
1To C
10, C more preferably
1To C
6, methyl more preferably, ethyl, propyl group (n-propyl or sec.-propyl), butyl (normal-butyl, the isobutyl-or the tertiary butyl) or amyl group (comprising n-pentyl and isopentyl), more preferably methyl.Be to be understood that, term " alkyl " comprises alkyl (branching or nonbranched) as used herein, the alkyl of replacement (branching or nonbranched), thiazolinyl (branching or nonbranched), the thiazolinyl (branching or nonbranched) that replaces, alkynyl (branching or nonbranched), the alkynyl of replacement (branching or nonbranched), cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group of replacement, the cycloalkynyl radical of cycloalkynyl radical and replacement.
As used herein, term " low alkyl group " for example is meant, branching or nonbranched, and ring-type or acyclic, saturated or undersaturated (as alkenyl or alkynyl) alkyl, wherein said cyclic low-grade alkyl is C
5, C
6Or C
7, and wherein said acyclic low alkyl group is C
1, C
2, C
3Or C
4, and be preferably selected from methyl, ethyl, propyl group (n-propyl or sec.-propyl) or butyl (normal-butyl, sec-butyl, isobutyl-or the tertiary butyl).Should be appreciated that term " low alkyl group " comprises low alkyl group (branching or nonbranched) as used herein, low-grade alkenyl (branching or nonbranched), low-grade alkynyl (branching or nonbranched), ring low alkyl group, ring low-grade alkenyl and ring low-grade alkynyl.
Alkyl and aryl can be replacements or unsubstituted.Under situation about replacing, will there be for example 1 to 3 substituting group usually, preferred 1 substituting group.Substituting group for example can comprise: carbon-containing group such as alkyl, aryl, arylalkyl (as replacing and unsubstituted phenyl, replacing and unsubstituted benzyl); Halogen atom and halogen-containing group such as haloalkyl (as trifluoromethyl); Oxy radical is as alcohol (as hydroxyl, hydroxyalkyl, aryl (hydroxyl) alkyl), ether (as alkoxyl group, aryloxy, alkoxyalkyl, aryloxy alkyl), aldehyde (as formaldehyde), ketone is (as alkyl-carbonyl, the alkyl-carbonyl alkyl, aryl carbonyl, aromatic yl alkyl carbonyl, the aromatic carbonyl alkyl), acid (as carboxyl, carboxyalkyl), acid derivative such as ester are (as carbalkoxy, alkoxycarbonyl alkyl, alkyl carbonyl oxy, alkyl carbonyl oxy alkyl), amides is (as aminocarboxyl, single-or two-alkyl amino-carbonyl, the aminocarboxyl alkyl, single-or two-alkyl amino alkyl carbonyl, aromatic yl aminocarbonyl), carbamate (as alkoxycarbonyl amido, aryloxy carbonyl amino, amino carbonyl oxygen base, single-or two-alkyl amino carbonyl oxy, arylamino carbonyl oxygen base) and ureas (as singly-or two-alkyl amino-carbonyl amino or aromatic yl aminocarbonyl amino); Nitrogen-containing group such as amine (as amino, single-or two-alkylamino, aminoalkyl group, single-or two-alkylamino alkyl), trinitride, nitrile (as cyano group, the cyano group alkyl), nitro; Sulfur-containing group such as mercaptan, thioether, sulfoxide and sulfone are (as alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylthio alkyl, the alkyl sulphinyl alkyl, the alkyl sulphonyl alkyl, arylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio alkyl, aryl sulfonyl kia alkyl, aryl sulfonyl alkyl); With contain one or more, preferred 1 heteroatomic heterocyclic group (as thienyl, furyl, pyrryl; imidazolyl, pyrazolyl, thiazolyl, isothiazolyl oxazolyl ， oxadiazole base, thiadiazolyl group, aziridinyl; azetidinyl, pyrrolidyl, pyrrolinyl, imidazolidyl; imidazolinyl, pyrazolidyl, tetrahydrofuran base, pyranyl; the pyrans ketone group, pyridyl, pyrazinyl, pyridazinyl; piperidyl, six hydrogen azepine bases, piperazinyl, morpholinyl; the thia naphthyl, benzofuryl, isobenzofuran-base, indyl; the oxindole base, pseudoindoyl, indazolyl, indolinyl; the 7-azaindolyl, benzopyranyl, tonka bean camphor base, isocoumarinyl; quinolyl, isoquinolyl, naphthyridine base (naphthridinyl); the cinnolines base, quinazolyl, pyridopyridine base, benzoxazinyl; quinoxalinyl, chromenyl, chromanyl; the isochroman base, 2 base and carbolinyl).
Unless specifically note in addition, ring is an isocyclic.
Low alkyl group can be replacement or unsubstituted, preferably unsubstituted.Under situation about replacing, will there be for example 1 to 3 substituting group usually, preferred 1 substituting group.
As used herein, term " alkoxyl group " for example is meant, alkyl-O-, and " alkyloyl " for example is meant alkyl-CO-.Alkoxy substituent or the substituting group that contains alkoxyl group can be replaced by for example one or more alkyl.
As used herein, term " halogen " is meant for example fluorine, chlorine, bromine or iodine base, preferred fluorine, chlorine or bromine base, and more preferably fluorine or chlorine base.
As used herein, term " pharmaceutical salts " is meant any pharmaceutical salts of formula (I) compound.Salt can be by medicinal nontoxic bronsted lowry acids and bases bronsted lowry preparation, and described bronsted lowry acids and bases bronsted lowry comprises inorganic and organic bronsted lowry acids and bases bronsted lowry.Such acid for example comprises, acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid, dichloro acetic acid, formic acid, fumaric acid, glyconic acid, L-glutamic acid, urobenzoic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, oxalic acid, pamoic, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, oxalic acid, tosic acid etc.Particularly preferably be fumaric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, succsinic acid, sulfuric acid and methylsulfonic acid.Acceptable alkali salt comprises basic metal (as sodium, potassium), alkaline-earth metal (as calcium, magnesium) and ammonium salt.
More specifically, the present invention relates to a kind of pharmaceutical composition, it comprises the compound according to formula (I) for the treatment of significant quantity:
Wherein
Q is unsubstituted phenyl,
The phenyl that replaces, its for be independently selected from halogen, low alkyl group ,-COOA ,-CF
3,-OA ,-NC (=O) the group list in A and the phenyl-, two-or trisubstd phenyl,
Unsubstituted heterocyclic, it is 5-or 6-unit heteroaromatic rings, described heteroaromatic rings connects and contains 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The heterocyclic radical that replaces, it is the heterocyclic radical that quilt-COOA or halogen replace,
Naphthyl,
9-and the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, it connects and contains 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The bicyclic heterocyclic radical that replaces, it be 9-or 10-unit bicyclic heterocyclic radical, described bicyclic heterocyclic radical be selected from substituting group list in halogen or the low alkyl group-, two-or three-replacement;
R
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN(A)A，
-DOA; Or
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional another heteroatoms that is selected among N, O and the S that contains, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement;
A is the low alkyl group that contains 1 to 4 carbon atom,
B is that 3-to 7-unit replaces or unsubstituted carbocyclic ring saturated rings,
D is the bivalent form of A,
E is saturated, the unsaturated or undersaturated heterocycle of part of 5-or 6-unit, and described heterocycle contains 1 to 3 heteroatoms that is selected among S, N and the O,
N is 0 or 1,
Condition is, at R
1Or R
2For H and another are under the situation of low alkyl group, and at Q in contraposition by halogen under the mono-substituted situation, described halogen is a chlorine,
Condition is, at R
1Or R
2For H and another are under the situation of low alkyl group, and at Q in contraposition by low alkyl group under the mono-substituted situation, described low alkyl group contains 1 to 3 carbon atom,
Condition is, at R
1Or R
2For H and another are under the situation of CH2B, and Q be wherein phenyl a position by the situation of the mono-substituted substituted-phenyl of halogen under, described halogen is not Cl,
Condition is, at R
1Or R
2For H and another are the phenyl that D-replaces, wherein D is-CH
2CH
2-and phenyl at the ortho position by F under the mono-substituted situation, and Q be wherein phenyl by the situation of the mono-substituted substituted-phenyl of halogen under, the halogen in a position is not Cl,
Condition is, at R
1Or R
2For H and another are-phenyl that D-replaces, wherein D is-CH
2-, and phenyl replaced by the low alkyl group list, and this low alkyl group is adjacent-CH
3Situation under, and be under the situation of the substituted-phenyl that replaced by halogen of phenyl at Q, be not Cl at the adjacent halogen, or its pharmaceutical salts,
And pharmaceutical carrier.
In another embodiment of the invention, a kind of method for the treatment of the patient's who needs the treatment type ii diabetes type ii diabetes is provided, this method comprises the compound according to formula (I) to described patient's drug treatment significant quantity.
Preferably aforesaid pharmaceutical composition, wherein
Q is unsubstituted phenyl,
The phenyl that replaces, its for be independently selected from halogen, low alkyl group ,-COOA ,-CF3 ,-OA ,-NC (=O) the group list in A and the phenyl-, two-or trisubstd phenyl, and wherein
R
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH
2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN (A) A and
-DOA。
Further preferably aforesaid pharmaceutical composition, wherein
Q is a unsubstituted heterocyclic, and it is 5-or 6-unit heteroaromatic rings, and described heteroaromatic rings connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The heterocyclic radical that replaces, it is the heterocyclic radical that quilt-COOA or halogen replace,
Naphthyl, and wherein
R
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted
Carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH
2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN (A) A and
-DOA。
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein Q is 9-and the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, and it connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The bicyclic heterocyclic radical that replaces, it be 9-or 10-unit bicyclic heterocyclic radical, described bicyclic heterocyclic radical be selected from substituting group list in halogen or the low alkyl group-, two-or three-replacement; Wherein
R
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH
2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN (A) A and
-DOA。
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein Q is unsubstituted phenyl,
The phenyl that replaces, its for be independently selected from halogen, low alkyl group ,-COOA ,-CF
3,-OA ,-NC (=O) the group list in A and the phenyl-, two-or trisubstd phenyl; Wherein
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional another heteroatoms that is selected among N, O and the S that contains, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, wherein Q is a unsubstituted heterocyclic, it is 5-or 6-unit heteroaromatic rings, and described heteroaromatic rings connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom
The heterocyclic radical that replaces, it is the heterocyclic radical that quilt-COOA or halogen replace,
Naphthyl; Wherein
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional another heteroatoms that is selected among N, O and the S that contains, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein Q is 9-and the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, and it connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The bicyclic heterocyclic radical that replaces, it be 9-or 10-unit bicyclic heterocyclic radical, described bicyclic heterocyclic radical be selected from substituting group list in halogen or the low alkyl group-, two-or three-replacement; Wherein
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional another heteroatoms that is selected among N, O and the S that contains, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and the described treatment significant quantity of wherein said compound is that about 10mg was to about 1000mg/ days.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein halogen is Cl or F.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein Q is unsubstituted thiophene, or is encircling quilt-COOCH on the carbon
3Or the heterocyclic radical of Cl list-replacement.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, wherein Q is 9-or the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, it is by the ring carbon atom connection and have 1 or 2 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen, or
The bicyclic heterocyclic radical that replaces, it is to have one or more substituent 9-or 10-unit bicyclic heterocyclic radicals that are selected from halogen or the low alkyl group.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein Q is selected from
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, wherein works as R
1Or R
2In one be H and another be mono-substituted or unsubstituted saturated mono-, two-or during 5 to 10 yuan of carbocyclic rings of three-ring, described saturated carbon ring is 5 or 6 yuan of monocycles or 10 yuan of three ring, and the carbocyclic ring of wherein list-replacement is described by the saturated carbon ring of low alkyl group list-replacement.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, wherein works as R
1Or R
2In one be H and another during for undersaturated 9-of dicyclo part or 10-unit ring, described ring is
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, wherein works as R
1Or R
2In one to be H and another be-CH
2During B, B is 3-or 6-unit carbocyclic ring saturated rings.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, wherein at R
1Or R
2In the situation of a phenyl that to be H and another replace for-D-phenyl or D-under ,-D-phenyl is-CH
2CH (CH
3)-phenyl ,-CH (CH
3)-phenyl, or-(CH
2) phenyl that replaces of n-phenyl and D-is-CH (CH
3)-(fluoro-phenyl) ,-CH
2CH
2-(fluoro-phenyl) ,-CH
2-(trifluoromethyl-phenyl) ,-CH
2-(methyl-phenyl) ,-(CH
2) p-(chloro-phenyl) ,-(CH
2) p-(methoxyl group-phenyl), or-(CH
2) p-(two-methoxyl group-phenyl),
Wherein n is 1,2 or 3, and
P is 1 or 2.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein A is a methyl.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, wherein at R
1Or R
2In one be H and another under the situation of DE, wherein D is-CH
2-or-CH
2CH
2-.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein Z is selected from:
Preferred Q is by chlorine or methyl substituted phenyl.More preferably Q is by chlorine or methyl substituted phenyl at the ortho position.Preferred Q is mono-substituted, and more preferably Q is 2-methyl-phenyl.Further preferably Q is a 2-chloro-phenyl.
In another preferred embodiment, Q has two or three to be selected from substituent phenyl in chlorine or the methyl.Preferred Q is 2-chloro-6-aminomethyl phenyl or 3-chloro-2-methyl-phenyl.Further preferably Q is unsubstituted phenyl.
In another preferred embodiment, Q is replacement or unsubstituted thienyl, or replacement or unsubstituted quinolines base.Preferred Q is unsubstituted thiophene-2-base or unsubstituted quinolines-8-base.
In another preferred embodiment, the phenyl of Q for being replaced by halogen in the 4-position.Preferred Q is 4-chloro-phenyl or 4-fluoro-phenyl.
In addition, R preferably
1Be hydrogen, and R
2Be diamantane-1-base.R further preferably
1Be hydrogen, and R
2Be cycloalkyl.
In another preferred embodiment, R
1, R
2The nitrogen that is connected with them is perhydro isoquinoline 99.9-2-base.R further preferably
1, R
2The nitrogen that is connected with them is perhydro quinoline-1-base.R further preferably
1Be hydrogen, and R
2Be 2-(thiophene-2-yl)-ethyl.
Another kind of preferred pharmaceutical composition as defined above is such pharmaceutical composition, and wherein said compound is:
R wherein
3For low alkyl group and m are 1,2 or 3.
In addition, R preferably
1Be hydrogen, and R
2Be the D-naphthyl.In addition, R preferably
1Or R
2One be H, and another is DE, E is selected from:
With
B can be as described above replaced by term aryl.Preferred B is the unsubstituted carbocyclic ring saturated rings of 3-to 7-unit.
Another embodiment of the invention relates to formula (I) compound as defined above.Preferred compound is to be selected from those following compounds:
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-methyl-cyclopentyl)-acid amides,
(3S)-([1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-[(cis)-1,3,3a, 4,7,7a-six hydrogen-isoindole-2-yl]-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-morpholine-4-base-ketone,
(3S)-(4aR, 8aS)-rel-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone,
(3S)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone,
(3S)-(7-aza-bicyclo [2.2.1] heptan-7-yl)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone,
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid diamantane-1-base acid amides,
(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopentyl amide,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4,4-dimethyl-piperidines-1-yl)-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4-methyl-piperidines-1-yl)-ketone,
(rac)-azepan-1-base-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-1-yl)-ketone,
(3S)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(3R)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(3S)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(3R)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4-hydroxy-piperdine-1-yl)-ketone,
(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
2-[3-(2-phenyl-propyl group formamyl)-piperidines-1-alkylsulfonyl]-methyl benzoate,
2-[3-(cyclohexyl methyl-formamyl)-piperidines-1-alkylsulfonyl]-methyl benzoate,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-5-trifluoromethyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2-chloro-5-trifluoromethyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2,3-dimethoxy-phenyl)-ethyl]-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-morpholine-4-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (1-phenyl-ethyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid isobutyl--acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid styroyl-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
2-[3-(2-thiophene-2-base-ethylamino formyl radical)-piperidines-1-alkylsulfonyl]-methyl benzoate,
3-[3-(2-methoxyl group-benzylamino formyl radical)-piperidines-1-alkylsulfonyl]-the thiophene-2-carboxylic acid methyl esters,
3-[3-(2-thiophene-2-base-ethylamino formyl radical)-piperidines-1-alkylsulfonyl]-the thiophene-2-carboxylic acid methyl esters,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid (2-acetylamino-ethyl)-acid amides,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-morpholine-4-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-tetramethyleneimine-1-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-diisopropylaminoethyl-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (pyridin-4-yl methyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(5-chloro-2-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(3-fluoro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2,3-dimethoxy-phenyl)-ethyl]-acid amides,
1-(3-fluoro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-acetylamino-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-acetylamino-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid (2-morpholine-4-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide; With the mixture of three fluoro-acetate,
1-(4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides; With the mixture of three fluoro-acetate,
1-(4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid sec.-propyl acid amides,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid methyl acid amides,
1-(5-chloro-3-methyl-benzo [b] thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (the 4-tertiary butyl-cyclohexyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid isobutyl--acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid styroyl-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-benzenesulfonyl-piperidines-3-carboxylic acid (1-methoxymethyl-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-benzenesulfonyl-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (3-methoxyl group-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl amide,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclopentyl amide,
1-benzenesulfonyl-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (the 4-tertiary butyl-cyclohexyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (1-phenyl-ethyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid styroyl-acid amides,
(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3,5,7-trimethylammonium-diamantane-1-yl)-acid amides and
(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-hydroxyl-diamantane-1-yl)-acid amides, or its pharmaceutical salts.
Particularly preferred compound is to be selected from those following compounds:
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl amide,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopentyl amide,
(rac)-azepan-1-base-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-1-yl)-ketone,
(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides and
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
Or its pharmaceutical salts.
Formula (I) compound is preferred separately, and its pharmaceutical salts is that separately preferably its Chinese style (I) compound is particularly preferred.
Therefore formula (I) compound can have one or more asymmetric C atoms, can be used as the enantiomerism mixture, the diastereo-isomerism mixture, or exist as optically pure compound.
Should be appreciated that general formula (I) compound among the present invention can derive at functional group place, so that the derivative that can change parent compound in vivo into to be provided.
As mentioned above, find that novel cpd of the present invention suppresses 11beta-Hydroxysteroid dehydrogenase.Therefore they can be used for the treatment of and prevent the disease by the adjusting of 11beta-Hydroxysteroid dehydrogenase inhibitor.Such disease comprises type ii diabetes and metabolism syndrome.
Therefore, the invention still further relates to pharmaceutical composition, it comprises compound and pharmaceutical carrier and/or assistant agent as defined above.
Equally, the present invention comprises aforesaid compound, it is as therapeutic active substance, especially the treatment of diseases active substance that is used for the treatment of and/or prevents to be regulated by the 11beta-Hydroxysteroid dehydrogenase inhibitor is in particular as the therapeutic active substance that is used for the treatment of and/or prevents type ii diabetes or metabolism syndrome.
In another preferred embodiment, the present invention relates to be used for the treatment of and/or disease that prophylactic treatment is regulated by the 11beta-Hydroxysteroid dehydrogenase inhibitor, especially for the method for the treatment of and/or preventing property treatment type ii diabetes or metabolism syndrome, this method comprises: compound is to human or animal's administration as defined above.
The present invention also comprises the disease, the particularly application in treating and/or preventing property treatment type ii diabetes or metabolism syndrome that compound is as defined above regulated by the 11beta-Hydroxysteroid dehydrogenase inhibitor in the treatment for the treatment of and/or preventing property.
The invention still further relates to the application of aforesaid compound in the preparation medicine, the disease that described medicine is used for the treatment of and/or prophylactic treatment is regulated by the 11beta-Hydroxysteroid dehydrogenase inhibitor is especially for treating and/or preventing property treatment type ii diabetes or metabolism syndrome.Such medicine comprises aforesaid compound.
Preventing and/or treating of type ii diabetes is preferred indication.
Synthesize according to the general of The compounds of this invention
Can prepare compound of the present invention by the mode of any routine.The proper method of synthetic these compounds is provided in an embodiment.Usually, can be according to the compound of scheme 1, scheme 2 or scheme 3 (referring to following) preparation formula I.The raw material sources that are used for these reactions have also been described.
According to scheme 1 preparation compound of the present invention
Scheme 1
The compound of formula 1 can be by nipecotic acid (2), according to scheme 1, obtain the sulphonamide of formula 4 by sulfonylation, then carry out the acid amides coupled reaction, and the compound that obtains formula 1 prepares.Can make the compound of formula 2 and the SULPHURYL CHLORIDE reaction of formula 3 by in inert solvent such as halohydrocarbon (as methylene dichloride) or ether (as tetrahydrofuran (THF) Huo diox) or ester solvent such as ethyl acetate, carry out first reaction.This reaction is eligibly carried out in the presence of organic bases (as triethylamine or diisopropylethylamine) or mineral alkali (as sodium hydroxide or yellow soda ash).When using organic bases, this reaction is eligibly carried out in the presence of water extra, and this cosolvent should be stable to alkaline aqueous solution.This reaction can preferably be carried out in about room temperature in the temperature between about 0 ℃ and the about room temperature.
In addition, the aryl-alkylsulfonyl-nipecotic acid derivative of a large amount of formulas 4 is commercially available, and in them some are shown in the following table:
| Title | Supplier |
| 1-[(2,4, the 6-trimethylphenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | AsInEx，Moscow，Russia |
| The 1-[(2-nitrophenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | Ambinter，Paris，France |
| The 1-[(4-bromophenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | Interchim，Montlucon，France |
| The 1-[(4-ethoxyl phenenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | Enamine，Kiev，Ukraine |
| The 1-[(4-fluorophenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | Interchim，Montlucon，France |
| The 1-[(4-p-methoxy-phenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | ChemDiv，San Diego，USA |
| The 1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | AKos Consulting，Basel， Switzerland |
| The 1-[(4-nitrophenyl) alkylsulfonyl]-the 3-piperidine carboxylic acid | Interchim，Montlucon，France |
| 1-[[4-(acetylamino) phenyl] alkylsulfonyl]-the 3-piperidine carboxylic acid | Enamine，Kiev，Ukraine |
Can use for the known method of those of ordinary skills according to the coupling of the amine of the carboxylic acid of the formula 4 of scheme 1 and formula 5 and to carry out.For example, if necessary its many examples itself are known coupler in chemistry of peptides in the presence of, the amine of the carboxylic acid of through type 4 or its appropriate derivative such as Acibenzolar and formula 5 or their corresponding acid salt (for example, hydrochloride) reaction can be carried out this conversion.By alkali such as the diisopropylethylamine that is suiting, coupler such as O-(benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate exists down, and in the presence of choosing wantonly of the material that improves speed of reaction such as I-hydroxybenzotriazole or 1-hydroxyl-7-azepine benzotriazole is other, at inert solvent such as hydrochloric ether (for example, methylene dichloride) or N, in dinethylformamide or the N-Methyl pyrrolidone, the temperature between about 0 ℃ and about room temperature is preferably in about room temperature, handle the carboxylic acid of formula 4 with the hydrochloride of formula 5 amine, eligibly carry out this reaction.Alternatively, be transformed into activate ester derivative such as N-hydroxy-succinamide ester, with the amine or the corresponding acid addition salt reaction of itself and formula 5, can carry out this reaction subsequently by carboxylic acid with formula 4.Can be at coupler such as N, N '-dicyclohexylcarbodiimide exists down, and in inert solvent such as tetrahydrofuran (THF), the temperature between about 0 ℃ and about room temperature is reacted the carboxylic acid of formula 4 and N-hydroxy-succinamide, carries out this reaction sequence.Then, at alkali such as organic bases (for example, triethylamine or diisopropylethylamine etc.), at suitable inert solvent such as N, dinethylformamide in about room temperature, is handled the N-hydroxy-succinamide ester that obtains with the amine or the corresponding acid salt of formula 5.
According to scheme 2 preparations compound of the present invention
Scheme 2
For aryl-alkylsulfonyl and amido are incorporated in the molecule, can also prepare the compound of formula 1 of the present invention according to the scheme 2 different with scheme 1.In this method, the nitrogen of protection 2 compounds obtains the compound of formula 6, and wherein PG represents blocking group, and is wherein as described below, and the many suitable example of blocking group it is known to those skilled in the art that.Then, the compound of formula 6 is converted into the acid amides of formula 7, the blocking group that dissociates then obtains the amine of formula 8, then with the SULPHURYL CHLORIDE reaction of this compound and formula 3, obtains the compound of formula 1.To those skilled in the art, what understand easily is, scheme 2 is provided at the possibility of the amine 5 preparation The compounds of this invention of solid phase by using resin-bonded, in The compounds of this invention, and R
1Or R
2In one the expression hydrogen.
Many blocking group PG are known for the technician in the organic synthesis field.For example, several suitable blocking groups are recited in " Protective Groups in Organic Synthesis " [Greene, T.W. and Wuts, P.G.M., 2nd Edition, John Wiley﹠amp; Sons, N.Y.1991] in.Preferred blocking group is and those the compatible blocking groups of reaction conditions that are used for preparing The compounds of this invention.The example of such blocking group has: tertbutyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).
As shown in the table, some examples of formula 6 intermediates have: commercially available.Can as the back one paragraph described in, the further example of preparation formula 6 intermediates.
| The compound title | Supplier |
| (3R)-1-(9-fluorenylmethyloxycarbonyl)-3-piperidine carboxylic acid | Fluka Chemical Corp.，Milwaukee，WI |
| (3R)-1-(tertbutyloxycarbonyl)-3-piperidine carboxylic acid | Fluka Chemical Corp.，Milwaukee，WI |
| (3S)-1-(tertbutyloxycarbonyl)-3-piperidine carboxylic acid | Digital Specialty Chemicals，Dublin，NH |
| 1-(9-fluorenylmethyloxycarbonyl)-3-piperidine carboxylic acid | Fluka Chemical Corp.，Milwaukee，WI |
| 1-(tertbutyloxycarbonyl)-3-piperidine carboxylic acid | Aldrich Chemical Company，Milwaukee， WI |
| The 1-[(benzyloxy) carbonyl]-the 3-piperidine carboxylic acid | Maybridge plc，Tintagel，Cornwall，UK |
(it organically (for example can be at alkali, triethylamine) or inorganic (for example, sodium hydroxide, yellow soda ash or salt of wormwood, or sodium bicarbonate)) exist down, in inert solvent such as water Huo diox or tetrahydrofuran (THF), or at mixture such as the water and the acetone of inert solvent, water is with diox, or in the mixture of water and tetrahydrofuran (THF), make compound and the earbalkoxylation reagent such as the tert-Butyl dicarbonate of formula 2,2-(tertiary butyloxycarbonyl oxygen base imino-)-2-phenylacetonitrile, chloroformic acid benzyl ester, 9-fluorenyl methyl pentafluorophenyl group carbonic ether, reactions such as N-(9-fluorenyl methoxy carbonyl oxygen base) succinimide, intermediate that can preparation formula 6.This reaction is the temperature between about 0 ℃ and about room temperature eligibly, preferably carries out in about room temperature.At the intermediate of formula 6 for alkaline condition under the unsettled situation, under the situation as formula 6 compounds of representing Fmoc (9-fluorenylmethyloxycarbonyl) at PG, should be careful be that this intermediate is not exposed to strong alkaline condition in attempting its process of preparation.For what those skilled in the art understood easily be; the character of target compound 1 is depended in the selection of blocking group; thereby for example, the functional group that exists in NR1R2 part is compatible with the condition that is used for being converted at formula 7 compounds the removal that realizes blocking group in formula 8 compounds.Because there are a large amount of different selections in the compensation process for blocking group PG and deprotection,, select blocking group to have no problem for according to scheme 2 synthetic any compounds of the present invention.
Can use for the known method of those of ordinary skills according to the coupling of the amine of the carboxylic acid of the formula 6 of scheme 2 and formula 5 and to carry out.For example, if necessary its many examples itself are known coupler in chemistry of peptides in the presence of, the amine of the carboxylic acid of through type 6 or its appropriate derivative such as Acibenzolar and formula 5 or their corresponding acid salt (for example, hydrochloride) reaction can be carried out this conversion.By alkali such as the diisopropylethylamine that is suiting, coupler such as O-(benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate exists down, and in the presence of choosing wantonly of the material that improves speed of reaction such as I-hydroxybenzotriazole or 1-hydroxyl-7-azepine benzotriazole is other, at inert solvent such as hydrochloric ether (for example, methylene dichloride) or N, in dinethylformamide or the N-Methyl pyrrolidone, the temperature between about 0 ℃ and about room temperature is preferably in about room temperature, handle the carboxylic acid of formula 6 with the hydrochloride of formula 5 amine, eligibly carry out this reaction.Alternatively, be transformed into activate ester derivative such as N-hydroxy-succinamide ester, with the amine or the corresponding acid addition salt reaction of itself and formula 5, can carry out this reaction subsequently by carboxylic acid with formula 6.Can be at coupler such as N, N '-dicyclohexylcarbodiimide exists down, and in inert solvent such as tetrahydrofuran (THF), the temperature between about 0 ℃ and about room temperature is reacted the carboxylic acid of formula 6 and N-hydroxy-succinamide, carries out this reaction sequence.Then, at alkali such as organic bases (for example, triethylamine or diisopropylethylamine etc.), at suitable inert solvent such as N, dinethylformamide in about room temperature, is handled the N-hydroxy-succinamide ester that obtains with the amine or the corresponding acid salt of formula 5.
According to known program in synthetic chemistry and the chemistry of peptides field, carry out being converted into removing of blocking group in the amine of formula 8, and described program depends on the character of blocking group PG at formula 7 compounds.Many examples of suitable program are listed in " Protective Groups in Organic Synthesis ", [Greene, T.W. and Wuts, P.G.M., 2nd Edition, John Wiley﹠amp; Sons, N.Y.1991] in.For example, be under the situation of Fmoc (9-fluorenylmethyloxycarbonyl) at blocking group, by at inert solvent such as N; in dinethylformamide or the methylene dichloride,, use organic bases (as piperidines in about room temperature; morpholine, or thanomin) processing formula 7 compounds, can eligibly remove this group.At blocking group is under the situation of benzyloxycarbonyl (Cbz); under the condition of hydrogenolysis; for example carry in the presence of palladium or the palladium black at noble metal catalyst such as carbon; at inert solvent (for example; alcohol is as ethanol) exist time, in about room temperature and under atmospheric pressure, or if desired under elevated pressure (as the hydrogen of 50PSI); by hydrogenation, can remove this group.As further example, be under the situation of tertbutyloxycarbonyl (Boc) at blocking group, by in inert solvent,, can remove this group with acid (organic or inorganic) processing formula 7 compounds.For example, can be by in methylene dichloride, in about room temperature, handle formula 7 compounds with trifluoroacetic acid, remove the Boc group, perhaps can (for example pass through at alcoholic solvent, methyl alcohol or ethanol) or ether (for example ， diox) or ethyl acetate in, also in about room temperature, with salt acid treatment formula 7 compounds, remove it.
By sulfonylation, the compound of formula 8 is converted into suitablely the compound of formula 1 of the present invention with the sulfonylation agent of formula 3.Can make the compound of formula 8 and the SULPHURYL CHLORIDE reaction of formula 3 by in inert solvent such as halohydrocarbon (as methylene dichloride) or ether (as tetrahydrofuran (THF) Huo diox) or ester solvent such as ethyl acetate, carry out this reaction.This reaction is eligibly carried out in the presence of organic bases (as triethylamine or diisopropylethylamine) or mineral alkali (as sodium hydroxide or yellow soda ash).When using mineral alkali, this reaction is eligibly carried out in the presence of water extra, and this cosolvent should be stable to alkaline aqueous solution.This reaction can preferably be carried out in about room temperature in the temperature between about 0 ℃ and the about room temperature.Many SULPHURYL CHLORIDE of formula 3 are commercially available, or can be synthetic according to aforesaid many diverse ways.
Under the situation of the amine of the resin-bonded of use formula 5, be converted into compound of the present invention for compound with the resin-bonded of formula 1, need extra step; That is, compound of the present invention and resin must be dissociated.This can use the condition of any routine to carry out, and many in these conditions are known for the technician in the solid phase organic synthesis field, and this condition depends on the character that product is connected to the joint on the solid carrier.For example, under the condition of using the FMBP resin,,, use organic acid, preferably handle the compound of the resin-bonded of formula 1, eligibly carry out this and dissociate with trifluoroacetic acid in room temperature by in inert solvent such as methylene dichloride.
According to scheme 3 preparations compound of the present invention
Scheme 3
Can also be according to scheme 3 preparations formula 1 compound of the present invention, scheme 3 is different from scheme 1 part and is, has extra two steps-protection step and the deprotection steps in the sequence.In this method, the carboxyl of protection 2 compounds obtains the compound of formula 9, wherein R
3The expression blocking group, as described below, the many suitable example of blocking group it is known to those skilled in the art that.Then, formula 9 compounds are converted into the sulphonamide of formula 10, the blocking group that dissociates then obtains the carboxylic acid of formula 4, and the amine coupling of this compound and formula 5 then obtains the compound of formula 1.It will be understood by those of skill in the art that scheme 3 is provided in solid phase by using the R of polymkeric substance carrying
3Group carries out the possibility of sulfonylation (formula 9 compounds are converted into formula 10 compounds).
Many blocking groups are known for the technician in the organic synthesis field.For example, several suitable blocking groups are recited in " Protective Groups in Organic Synthesis " [Greene, T.W. and Wuts, P.G.M., 2nd Edition, John Wiley﹠amp; Sons, N.Y.1991] in.Preferred blocking group is and those the compatible blocking groups of reaction conditions that are used for preparing The compounds of this invention.The example of such blocking group has: low alkyl group straight or branched ester (for example, methoxyl group (R
3=OCH
3), oxyethyl group (R
3=OCH
2CH
3), or tert.-butoxy (R
3=OC (CH
3)
3) ester), or benzyl ester (R
3=OCH
2C
6H
5), or in solid phase synthesis normally used resin (for example, Wang resin or Rink resin), and these can be undertaken by the method for any routine.For example, they can be prepared by any esterification by the carboxylic acid of corresponding formula 2, and many in them are known for those of ordinary skill in the art.For example, R wherein
3Formula 9 compounds of expression methoxyl group can be prepared by handling with the ethereal solution of diazomethane by formula 2 compounds.This reaction is eligibly in inert solvent such as ether (for example, diethyl ether or tetrahydrofuran (THF)) or alcohol (for example, methyl alcohol), and the temperature between about 0 ℃ and about room temperature is preferably carried out at about 0 ℃.At R
3Under the situation of expression Wang resin, by in the presence of coupler (as DIC), and N at catalytic amount, N-dimethyl aminopyridine (DMAP) exists down, at inert solvent such as N, in the dinethylformamide, in about room temperature, with this resin of formula 2 compound treatment, and the compound of preparation formula 9 eligibly.
Can make the compound of formula 9 and the SULPHURYL CHLORIDE reaction of formula 3 by in inert solvent such as halohydrocarbon (as methylene dichloride) or ether (as tetrahydrofuran (THF) Huo diox) or ester solvent such as ethyl acetate, carry out this sulfonylation.This reaction is eligibly carried out in the presence of organic bases (as triethylamine or diisopropylethylamine) or mineral alkali (as sodium hydroxide or yellow soda ash).When using mineral alkali, this reaction is eligibly carried out in the presence of water extra, and this cosolvent and blocking group should be stable to alkaline aqueous solution.This reaction can preferably be carried out in about room temperature in the temperature between about 0 ℃ and the about room temperature.Many SULPHURYL CHLORIDE of formula 3 are commercially available, or can be synthetic according to aforesaid many diverse ways.
In order to remove blocking group from formula 10 compounds, can adopt the mode of any routine to obtain the carboxylic acid of formula 4.For example, at R
3(for example represent nonbranched lower alkoxy, methoxyl group) under the situation, can be by in the mixture of The suitable solvent such as tetrahydrofuran (THF), first alcohol and water, with alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide, preferred lithium hydroxide is handled formula 10 compounds, carries out this reaction.This reaction is the temperature between about 0 ℃ and about room temperature eligibly, preferably carries out in about room temperature.At R
3Under the situation of expression Wang resin or Rink resin, can in methylene dichloride,, use trifluoroacetic acid to carry out this and dissociate in about room temperature.
Can be as mentioned above, use for the known method of those of ordinary skills and carry out coupling according to the amine of the carboxylic acid of the formula 4 of scheme 3 and formula 5, obtain the compound of formula 1 of the present invention.For example, if necessary its many examples itself are known coupler in chemistry of peptides in the presence of, the amine of the carboxylic acid of through type 4 or its appropriate derivative such as Acibenzolar and formula 5 or their corresponding acid salt (for example, hydrochloride) reaction can be carried out this conversion.By alkali such as the diisopropylethylamine that is suiting, coupler such as O-(benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate exists down, and the material that improves speed of reaction as I-hydroxybenzotriazole or 1-hydroxyl-7-azepine benzotriazole optional other in the presence of, at inert solvent such as hydrochloric ether (for example, methylene dichloride) or N, in dinethylformamide or the N-Methyl pyrrolidone, the temperature between about 0 ℃ and about room temperature is preferably in about room temperature, handle the carboxylic acid of formula 4 with the hydrochloride of formula 5 amine, eligibly carry out this reaction.Alternatively, be transformed into activate ester derivative such as N-hydroxy-succinamide ester, with the amine or the corresponding acid addition salt reaction of itself and formula 5, can carry out this reaction subsequently by carboxylic acid with formula 4.Can be at coupler such as N, N '-dicyclohexylcarbodiimide exists down, and in inert solvent such as tetrahydrofuran (THF), the temperature between about 0 ℃ and about room temperature is reacted the carboxylic acid of formula 4 and N-hydroxy-succinamide, carries out this reaction sequence.Then, at alkali such as organic bases (for example, triethylamine or diisopropylethylamine etc.), at suitable inert solvent such as N, dinethylformamide in about room temperature, is handled the N-hydroxy-succinamide ester that obtains with the amine or the corresponding acid salt of formula 5.
The source of the nipecotic acid of racemize or optically pure formula 2
The racemize nipecotic acid is purchased from supplier such as Aldrich Chemical Company, Inc., Milwaukee, WI; TCI America, Portland, OR; With Lancaster Synthesis Ltd., Lancashire, UK.Optically pure nipecotic acid also is commercially available.For example, (R)-(-)-piperidine carboxylic acid and (S)-(+)-nipecotic acid is all available from following supplier:
·Aldrich Chemical Company，Inc.，Milwaukee，WI
·Digital Specialty Chemicals，Dublin，NH
·TCI Japan，Tokyo，Japan
·Yamakawa Chemical Industry Co.，Ltd.，Tokyo，Japan.
In addition, the independent enantiomer of nipecotic acid can prepare by chiral chromatography (referring to J.S.Valsborg and C.Foged, J.Labelled Compd.Radiopharm.1997,39,401) or by splitting.Following publication has been described by splitting the preparation method of (R)-(-)-nipecotic acid and (S)-(+)-nipecotic acid or their acid salt:
M.Akkerman etc., Recueil Trav.Chim.Pays-Bas 1951,70,899
P.Magnus and L.S.Thurston J.Org.Chem.1991,56,1166
X.Zheng etc., Chirality 1995,7, and 90
S.Schleich and G.Helmchen, Eur.J.Org.Chem.1999,2515
Chung, Y.J. etc., J.Am.Chem.Soc.2000,122,3995
S.H.Gellman and B.R.Huck, US 6,710, and 186
E.D.Moher etc., WO 2002068391
K.A.Ismail and S.C.Bergmaier, Eur.J.Med.Chem.2002,37,469
The source of the SULPHURYL CHLORIDE of formula 3
The SULPHURYL CHLORIDE of formula 3 can be bought, and is perhaps following listed, and they can use a kind of preparation the in the known a large amount of various synthesis program in organic synthesis field.The route of synthesis of SULPHURYL CHLORIDE is complementary normally, and is provided at the path that has the SULPHURYL CHLORIDE of many different substitute modes in the aryl rings system.
The SULPHURYL CHLORIDE that surpasses 100 kinds of formulas 3 is commercially available from supplier such as Aldrich ChemicalCompany, Inc. (Milwaukee, WI), Lancaster Synthesis Ltd. (Lancashire, UK), (Portland is OR) with Maybridge plc (Tintagel for TCI America, Cornwall, UK).Illustrative purposes for example, a large amount of commercially available SULPHURYL CHLORIDE are shown in the following table.By consult Available Chemicals Directory (MDL Information Systems, San Leandro, CA) or SciFinder (Chemical Abstracts Service, Columbus OH), can find many other examples.
| Title | Supplier |
| 1-naphthalene-SULPHURYL CHLORIDE | TCI America，Portland，OR |
| 2,4-two fluoro-benzene-SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2,5-two chloro-benzene-SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-chloro-6-methylbenzene-SULPHURYL CHLORIDE | Lancaster Synthesis Ltd.，Lancashire，UK |
| 2-chloro-benzene-SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-sym-trimethylbenzene-SULPHURYL CHLORIDE | Lancaster Synthesis Ltd.，Lancashire，UK |
| 3-chloro-2-methylbenzene-SULPHURYL CHLORIDE | Maybridge plc，Tintagel，Cornwall，UK |
| 3-nitro-benzene-SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 3-pyridine SULPHURYL CHLORIDE hydrochloride | Combi-Blocks，LLC，San Diego，CA |
| 4-methoxyl group-2,3,6-trimethylammonium-benzene-SULPHURYL CHLORIDE | Lancaster Synthesis Ltd.，Lancashire，UK |
| 8-quinoline-SULPHURYL CHLORIDE | Maybridge plc，Tintagel，Cornwall，UK |
| O-toluene-SULPHURYL CHLORIDE | TCI America，Portland，OR |
By as following listed, known reaction in the organic synthesis field, SULPHURYL CHLORIDE that also can preparation formula 3.
Scheme 4
For example, the SULPHURYL CHLORIDE of formula 3 can be prepared as shown in scheme 4 by the sulfonic acid of formula 11.The aryl sulfonic acid of formula 11 or the chlorination of its salt can be eligibly by the N at catalytic amount, the optional extra of dinethylformamide exists down, in the temperature that depends between about 0 ℃ and about 80 ℃ of chlorination reaction, it is handled with chlorizating agent such as thionyl chloride or phosphoryl chloride or phosphorus pentachloride carry out.Many examples of this reaction are known in the literature, as those examples of listing in following table.
| Isoquinoline 99.9-5-SULPHURYL CHLORIDE | A.Morikawa etc., J.Med.Chem.1989,32,42 |
| 2-ethoxycarbonyl-benzene sulfonyl chloride | X.Baucherel etc., WO 2002100810 |
| 4-n-butoxy benzene sulfonyl chloride | V.P.Sandanayaka etc., US 2002/0099035 |
| Benzothiazole-6-SULPHURYL CHLORIDE | S.A.Kunda etc., US 6,140, and 505 |
| 5-dimethylamino-2-methyl-benzene sulfonyl chloride | C.Wu J.Org.Chem.1998，63，2348 |
Scheme 5
The SULPHURYL CHLORIDE of formula 3 can be as shown in scheme 5, and the electrophilic aromatics of the aromatic substance of through type 12 replaces and prepares.As known to persons of ordinary skill in the art, this method is suitable for preparing the aryl sulfonyl chloride with specific substitute mode, for example, in phenyl ring, introduce the position for alkylsulfonyl to be that ortho position or contraposition exist adjacent/to the situation of direct substitution base.By in the aromatic substance that does not have to handle with chlorsulfonic acid in the presence of the solvent formula 12, with the temperature heating of mixture between about 70 ℃ and about 100 ℃, eligibly carry out this reaction then.Many examples of this reaction are known in the literature, as those examples of listing in following table.
| 5-ethanoyl-3-thiophene SULPHURYL CHLORIDE | A.Arduini etc., Tetrahedron Lett.2003,44,5755 |
| 3-bromo-5-isobutyl--thiophene-2-SULPHURYL CHLORIDE | V.Derdau etc., J.Org.Chem.2003,68,5168 |
| 2-chloro-4-ethyl-thiazole-5-SULPHURYL CHLORIDE | R.Wischnat etc., WO 03002546 |
| 4-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-benzene sulfonyl chloride | L.M.Lima etc., Bioorg.Med.Chem. 2002,10, and 3067 |
| 2,3-dihydro-6-methoxyl group-1H-indenes-5-SULPHURYL CHLORIDE | M.A.Aboud-Gharbia US 4,857,644 |
| 5-(1, the 1-dimethyl ethyl)-2-methyl-benzene sulfonyl chloride | Y.Christidis US 4,948,827 |
| 4-fluoro-2-methyl-benzene sulfonyl chloride | M.Pal etc., J.Med.Chem.2003,46,3975 |
| 1-methyl isophthalic acid H-pyrazoles-4-SULPHURYL CHLORIDE | P.J.Dollings etc., US 6,103, and 708 |
| [4-(chlorosulfonyl) phenyl]-carboxylamine, methyl esters | B.P.Clark US 6,482,824 |
| 1,2,3,4-tetrahydrochysene-6-methyl-2,4-dioxo-5-pyrimidine sulfonyl chlorine | V.V.Makarov etc., RU 2,204,555 (Chemical Abstracts CAN 140:93843) |
Scheme 6
The SULPHURYL CHLORIDE of formula 3 can also be prepared by the diazotization as shown in scheme 6/sulfonylation sequence by the aniline of formula 13.By in the presence of mineral acid example hydrochloric acid or sulfuric acid, in the temperature that is lower than 10 ℃, preferred about 0 ℃, aniline or its acid salt (example hydrochloric acid salt) of the formula 13 in the aqueous solution eligibly carry out diazotization reaction with alkali metal nitrites salts such as Sodium Nitrite processing.By using known all ingredients and condition in the organic synthesis field, the diazonium salt that so obtains can be converted into SULPHURYL CHLORIDE.According to the program (US 6,531,605) of P.J.Hogan, the example of suitable reagent is included in sulfurous gas and cuprous chloride (I) or the cupric chloride (II) in the acetic acid/water, or the thionyl chloride in water and cuprous chloride (I) or cupric chloride (II).For example, sulfonylation can be by in suitable inert solvent such as Glacial acetic acid, at about 0 ℃, the solution of the diazonium salt of preparation as mentioned above joined in the mixture of sulfurous gas and cupric chloride (II) and carry out.Many examples of this reaction are known in the literature, as those examples of listing in following table.
| 4-methyl-benzene sulfonyl chloride | N.Ikemoto etc., Tetrahedron 2003,59, and 1317 |
| 3,4,5-trimethoxy-benzene sulfonyl chloride | C.Binisti etc., Eur.J.Med.Chem. 2001,36, and 809 |
| 2-fluoro-6-trifluoromethyl-benzene sulfonyl chloride | M.A.Gonzalez and E.W.Otterbacher US 6,433,169 |
| 2-methoxyl group-pyridine-5-SULPHURYL CHLORIDE | S.L.Gwaltney etc., Bioorg.Med. Chem.Lett.2001,11,871 |
| 3-nitro-benzene sulfonyl chloride | M.Meier and R.Wagner US 5,436,370 |
| 4-benzyloxy-2-nitro-benzene sulfonyl chloride | R.J.Chemey etc., J.Med.Chem. 2003,46, and 1811 |
| 4-ethanoyl-benzene sulfonyl chloride | A.S.Wagman etc., J.Org.Chem. 2000,65, and 9103 |
Scheme 7
The SULPHURYL CHLORIDE of formula 3 also can be prepared by the oxidisability chlorination reaction as shown in scheme 7 by the aryl benzyl thioether of formula 14.By in the mixture of The suitable solvent such as acetate and water, in the temperature of about room temperature, the chlorine bubbling is gone in the solution or suspension of aryl benzyl thioether of formula 14, eligibly carry out this reaction.
| 4-(chlorosulfonyl)-3-nitro-phenylformic acid, methyl esters | S.P.Andrews etc. .Org.Chem.2003,68,5525 |
| 4,7-two chloro-quinoline-6-SULPHURYL CHLORIDE | R.H.Baker etc., J.Am.Chem.Soc. 1946,68, and 2636 |
| 1,3-dioxo-2,3-dihydro-2-methyl isophthalic acid H-isoindole 4-4-SULPHURYL CHLORIDE | J.V.Hay etc., US 4,521, and 241 |
| 2,3-dihydro-1-oxo-1H-indenes-5-SULPHURYL CHLORIDE | J.J.Howbert and T.A.Crowell Synthetic Commun.1990,20,3193 |
| 5-(2-chlorosulfonyl-phenyl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-carboxylic acid, ethyl ester | W.J.Barry and I.L.Finar J.Chem.Soc. 1954,138 |
| 3-methyl-4-nitro-benzene sulfonyl chloride | J.C.Baum etc., Can.J.Chem.1990,68,1450 |
Scheme 8
The SULPHURYL CHLORIDE of formula 3 also can by the aryl bromide of formula 15, by metal-halogen exchange, make the reaction of organo-metallic intermediate and sulfurous gas obtain arylsulphonate as shown in scheme 8 then, then obtains aryl sulfonyl chloride with the sulfuryl chloride reaction and prepares.Can be by in the presence of choosing wantonly of Tetramethyl Ethylene Diamine (TMEDA) be extra, in suitable inert solvent such as tetrahydrofuran (THF) (THF) or diethyl ether, at low temperature (for example,-78 ℃ approximately), with organometallic reagent such as n-Butyl Lithium or preferred s-butyl lithium processing aryl bromide, to obtain the lithium aryl intermediate, carry out this reaction.Then with the lithium aryl intermediate at the mixture that does not have under the isolating condition with sulfurous gas and solvent such as diethyl ether, also in low temperature reaction between ℃ peace treaty-60 ℃ according to appointment-78.Then, the arylsulphonate that obtains can not had under the situation of separation of intermediates yet, be converted into aryl sulfonyl chloride by handling with sulfuryl chloride in about 0 ℃ temperature.Many examples of this reaction are known in the literature, as those examples of listing in following table.
| 2-benzyloxy-5-methyl-benzene sulfonyl chloride | G.Papageorgiou etc., Tetrahedron 1999,55, and 237 |
| [2,2 '] thiophthene base-5-SULPHURYL CHLORIDE | M.F.Chan etc., Bioorg.Med.Chem. 1998,6, and 2301 |
| 2 '-methoxyl group-biphenyl-4-SULPHURYL CHLORIDE | W.R.Ewing etc., J.Med.Chem.1999,42,3557 |
| 4-(2-phenyl-2H-tetrazolium-5-yl)-benzene sulfonyl chloride | Y.Tamura etc., J.Med.Chem.1998,41,640 |
| 3-(2-p-methylphenyl-vinyl)-thiophene-2-SULPHURYL CHLORIDE | B.Raju etc., Bioorg.Med.Chem.Lett. 1997,7, and 939 |
| 3-trifluoromethyl-benzene sulfonyl chloride | T.Hamada and O.Yonemitsu Synthesis 1986,852 |
Scheme 9
The SULPHURYL CHLORIDE of formula 3 can be by the aryl mercaptan of formula 16, and the oxidation by the use chlorine as shown in scheme 9 prepares.For example, in about 0 ℃ temperature, can carry out this reaction by aryl mercaptan with the solution-treated formula 16 of chlorine in inert solvent such as Glacial acetic acid.For example, 4-(1H-tetrazolium-1-yl) phenyl] SULPHURYL CHLORIDE can be by using this program, prepares by known thiophenol 4-(1H-tetrazolium-1-yl)-benzenethiol (W.V.Curran etc., US 3,932,440).Several examples of this reaction are known in the literature, as those examples of listing in following table.
| The 2-[4-morpholinodithio SULPHURYL CHLORIDE | E.Vedejs etc., J.Org.Chem.2000,65,2309 |
| 5-(chlorosulfonyl)-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester | F.Suzuki etc., JP 06056792 Chemical Abstracts CAN 122:31573 |
| 5-amino-1H-1,2,4-triazole-3-SULPHURYL CHLORIDE | R.B.Shankar US 4,937,350 |
| 2-methyl-benzene sulfonyl chloride | G.E.Lepone US 4,454,135 |
Scheme 10
The SULPHURYL CHLORIDE of formula 3 can be prepared by the series reaction of listing in the scheme 10 by the phenol of formula 17.In inert solvent, in the presence of alkali, by with N, N '-dialkyl group thiocarbamyl chlorine reaction, the phenol of formula 17 can be converted into the O-aryl-N of formula 18, N '-dialkyl thiocarbamic acid ester.O-aryl-the N of the formula 18 that obtains, N '-dialkyl thiocarbamic acid ester can by at high temperature as resetting S-aryl-N into formula 19, N '-dialkyl thiocarbamic acid ester at about 250 ℃ of heating pure substances.Then, can be with the S-aryl-N of formula 19, N '-dialkyl thiocarbamic acid ester in about 0 ℃ temperature, uses the oxidation of chlorine, and is converted into the SULPHURYL CHLORIDE of formula 3 by in the mixture of suitable inert solvent such as formic acid and water.This method is used to prepare the application example of SULPHURYL CHLORIDE can be referring to V.Percec etc., J.Org.Chem.2001,66,2104.
The source of the amine of formula 5
The amine of formula 5 can be bought, and is perhaps following listed, and they can use a kind of preparation the in the known a large amount of various synthesis program in organic synthesis field.
The amine of several thousand kinds of formulas 5 is commercially available from supplier such as Aldrich Chemical Company, Inc. (Milwaukee, WI), Lancaster Synthesis Ltd. (Lancashire, UK), (Portland is OR) with Maybridge plc (Tintagel for TCI America, Cornwall, UK).Other example of amine can be found in Available Chemicals Directory (MDL Information Systems, SanLeandro, CA) or SciFinder (Chemical Abstracts Service, Columbus, OH).
The amine of formula 5 also can prepare by reaction known in the organic synthesis field, as at " Comprehensive Organic Transformations:A Guide to Functional GroupPreparations " [R.C.Larock, VCH Publishers, Inc., N.Y.1989, pages 385-438] and in " Advanced Organic Chemistry " [J.March, 3
RdEdition, WileyInterscience, NY, 1985] in those reactions of listing.
The amine of the resin-bonded of formula 5 (R wherein
2Expression can connect the resin of amine) can prepare by the reaction that those of ordinary skill in the solid phase organic synthesis field is familiar with.For example, the amine of formula 5 (R wherein
2Expression FMPB resin) can by in the presence of reductive agent such as triacetyl oxygen base sodium borohydride, in inert solvent such as halohydrocarbon (as 1, the 2-ethylene dichloride),, handle FMPB resin (20) with the primary amine of formula 21 and prepare according to scheme 11 in room temperature.
FMPB+R
1NH
2→FMPB-NHR
1
20 21 5(R
2＝FMPB)
Scheme 11
Can be shown in the following table by some examples of the amine of currently known methods preparation:
| Tetrahydrochysene-N-methyl-3-thiophenine, 1, the 1-dioxide | B.Loev J.Org.Chem.1961，26，4394 |
| Tetrahydrochysene-3-thiophenine, 1, the 1-dioxide | Thomas P.Johnston etc., J.Med.Chem. 1971,14, and 600 |
| 2-hexamethylene-1-thiazolinyl-ethamine | R.S.Coleman and J.A.Shah Synthesis 1999,1399 |
| The N-[(4-fluorophenyl) methyl]-phenylethylamine, hydrochloride | S.Casadio Bollettino Chimico Farmaceutico 1978，V117，P83-9 Chemical Abstracts CAN 90：16185 |
| 3-isopropoxide propyl amine | J.C.Little US 3,372,195 |
| Bridge-norcamphyl amine | R.F.Borch etc., J.Am.Chem.Soc. 1971,93, and 2897 |
| N-cyclopropyl-N-(2-thienyl methyl)-amine | N.R.Easton DE 1,568,438 |
| Two-(2-methoxyl group-ethyl)-amine | Monsanto Chm.Co.US 2,876,243 |
In addition, a series of amino methyl pyrazoles can use described reductive amination programs (R.F.Borch etc., J.Am.Chem.Soc.1971,93,2897) such as Borch, is begun to prepare by the commercially available pyrazoles-formaldehyde as shown in following table:
| Amine | Aldehyde | Aldehyde supplier |
| 1,3,5-trimethylammonium-1H-pyrazoles-4-methylamine | 1,3,5-trimethylammonium-1H-pyrazoles-4-formaldehyde | Maybridge plc，Tintagel，Cornwall， UK |
| 1,5-dimethyl-1H-pyrazoles-4-methylamine | 1,5-dimethyl-1H-pyrazoles-4-formaldehyde | Fluorochem Ltd.，Old Glossop， Derbyshire，UK |
| 1,3-dimethyl-1H-pyrazoles-4-methylamine | 1,3-dimethyl-1H-pyrazoles-4-formaldehyde | Acros Organics USA，Morris Plains，NJ |
| 5-chloro-1,3-dimethyl-1H-pyrazoles-4-methylamine | 5-chloro-1,3-dimethyl-1H-pyrazoles-4-formaldehyde | Key Organics Limited/Bionet Research，Camelford，UK |
| Amine | Aldehyde | Aldehyde supplier |
| 4-chloro-1-methyl isophthalic acid H-pyrazoles-3-methylamine | 4-chloro-1-methyl isophthalic acid H-pyrazoles-3-formaldehyde | Butt Park Ltd.，Bath，UK |
| 4-bromo-1-methyl isophthalic acid H-pyrazoles-3-methylamine | 4-bromo-1-methyl isophthalic acid H-pyrazoles-3-formaldehyde | Apollo Scientific Ltd.，Stockport， UK |
| 1-methyl isophthalic acid H-pyrazoles-4-methylamine | 1-methyl isophthalic acid H-pyrazoles-4-formaldehyde | Fluorochem Ltd.，Old Glossop， Derbyshire，UK |
| 1-ethyl-5-methyl isophthalic acid H-pyrazoles-4-methylamine | 1-ethyl-5-methyl isophthalic acid H-pyrazoles-4-formaldehyde | Fluorochem Ltd.，Old Glossop， Derbyshire，UK |
| 1-ethyl-3-methyl isophthalic acid H-pyrazoles-4-methylamine | 1-ethyl-3-methyl isophthalic acid H-pyrazoles-4-formaldehyde | Fluorochem Ltd.，Old Glossop， Derbyshire，UK |
| 1-ethyl-1H-pyrazoles-4-methylamine | 1-ethyl-1H-pyrazoles-4-formaldehyde | Fluorochem Ltd.，Old Glossop， Derbyshire，UK |
| 1-ethyl-1H-pyrazoles-2,5-dimethyl-4-methylamine | 1-ethyl-1H-pyrazoles-2,5-dimethyl-4-formaldehyde | N.D.Zelinsky Institute，Moscow， Russia |
| 1,3-dimethyl-1H-pyrazoles-5-methylamine | 1,3-dimethyl-1H-pyrazoles-5-formaldehyde | Maybridge plc，Tintagel，Cornwall， UK |
| 3-methyl isophthalic acid-propyl group-1H-pyrazoles-4-methylamine | 3-methyl isophthalic acid-propyl group-1H-pyrazoles-4-formaldehyde | Ost-West Handelsservice ， Zepemick，Germany |
| 4-bromo-1-methyl isophthalic acid H-pyrazoles-5-methylamine | 4-bromo-1-methyl isophthalic acid H-pyrazoles-5-formaldehyde | Maybridge plc，Tintagel，Cornwall， UK |
| 5-chloro-3-ethyl-1-methyl isophthalic acid H-pyrazoles-4-methylamine | 5-chloro-3-ethyl-1-methyl isophthalic acid H-pyrazoles-4-formaldehyde | Oakwood Products，Inc.，West Columbia，SC |
The general of amantadine synthesizes
The amine of formula 5 (R wherein
1Expression hydrogen, and R
2The diamantane that expression does not replace or replaces) be commercially available, or can be by the known method preparation of those of ordinary skills.The example of commercially available diamantane-1-base-amine is shown in the following table:
| Title | Supplier |
| The 1-amantadine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The 2-adamantanamine hydrochloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 3,5,7-trimethylammonium-1-amantadine | ChemDiv，Inc.，San Diego，CA |
| 3, two (1-the methylethyl)-1-adamantanamine hydrochlorides of 5- | MicroChemistry Ltd.，Moscow， Russia |
| 3-amino-1-adamantanol | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 3-cyclohexyl-1-adamantanamine hydrochloride | MicroChemistry Ltd.，Moscow， Russia |
| 3-ethyl-1-adamantanamine hydrochloride | Apin Chemicals Ltd.，Abingdon，UK |
| 3-ethyl-5,7-dimethyl-1-adamantanamine hydrochloride | MicroChemistry Ltd.，Moscow， Russia |
| 3-ethyl-5-methyl isophthalic acid-adamantanamine hydrochloride | MicroChemistry Ltd.，Moscow， Russia |
| 3-sec.-propyl-1-amantadine | Chembridge，San Diego，CA |
| 3-methyl isophthalic acid-adamantanamine hydrochloride | Ambinter，Paris，France |
| 3-n-propyl-1-amantadine | ChemDiv，Inc.，San Diego，CA |
| 3-Trifluoromethyl-1-adamantanamine hydrochloride | Interchim，Montlucon，France |
| 4-amino-1-adamantanol | MicroChemistry Ltd.，Moscow， Russia |
| 5-amino-2-adamantanol | MicroChemistry Ltd.，Moscow， Russia |
| 5-amino-3,7-dimethyl-diamantane-1-alcohol | MicroChemistry Ltd.，Moscow， Russia |
| (5-amino-3-methyl-diamantane-1-yl)-methyl alcohol | ChemDiv，Inc.，San Diego，CA |
| The Memantine hydrochloride | Sigma，St.Louis，MOI |
The amine of not commercially available formula 5 (R wherein
1Expression hydrogen, and R
2Represent diamantane unsubstituted or that replace) can use that known a large amount of different reactions prepare in the document.For example, the 2-amantadine derivative can by ketone is converted into oxime, then is reduced to amine and prepares by corresponding diamantane-2-ketone.These reactions can be used K.Banert etc., Chem.Ber.1986, and 119, the program described in the 3826-3841 is carried out.The 2-amantadine also can be as in D.Lenoir etc., J.Org.Chem.1971,36, described in the 1821-1826, by the former adamantanol of 4-alkyl-4-, by in the presence of sulfuric acid, obtain ethanamide with special (Ritter) reaction in the acetonitrile, then its water is obtained separating the 2-amantadine and prepare.
Amantadine can be used hofmann rearrangement or similarly react to prepare by corresponding 1-diamantane-carboxyl acylamide.The various conditions of carrying out this reaction are well known in the art, and have the open a large amount of publications that this reaction are used to prepare the 1-amantadine.In these, have in R.M.Moriarty etc., Synth.Commun.1988,18,1179 and G.Loudon etc., J.Org.Chem.1984,49, the hofmann rearrangement of the multivalence described in the 4272-4276 (hypervalent) iodo-mediation, with at G.L.Anderson etc., Synth.Commun.1988, the reaction of the hypochlorite of report mediation in 18,1967.The 1-amantadine can also use Ritter reaction, is begun by corresponding 1-adamantanol, and use the chloro-acetonitrile treatment under acidic conditions, and then the hydrolysis acid amides prepares.Use such method to prepare the 1-amantadine and be described in Synthesis 2000, among the 1709-1712 by A.Jirgensons etc.Alternatively, the 1-amantadine can be by corresponding 1-bromo-diamantane, or use be similar in special condition, then hydrolysis (referring to, K.Gerzon etc., J.Med.Chem.1963,6,760-763 or O.Cervinka etc., Collect.Czech Chem.Commun.1974,39,1592-1588), or by 1-bromo-diamantane and ethanamide reaction, then hydrolysis (referring to, K.Gerzon etc., J.Med.Chem.1967,10,603-606 prepares).Can by use bromine/triphenyl phosphine bromination hydroxyl-diamantane or by diamantane use bromine easily prepare 1-bromo-diamantane (referring to, J.G.Henkel etc., J.Med.Chem.1982,25,51-56).The 1-amantadine can also be by corresponding 1-adamantanol, by under acidic conditions, replacing hydroxyl with trinitride, the trinitride that then reduces prepare (referring to, T.Sasaki etc., J.Org.Chem.1977,42,3741-3743).
In the practice of the inventive method, can be with the combination of any or any The compounds of this invention in the The compounds of this invention of significant quantity or its pharmaceutical salts by any common and acceptable method as known in the art administration alone or in combination.Therefore, can be with compound or composition administration in the following manner: oral (for example, oral cavity), the hypogloeeis, parenteral (for example, intramuscular, intravenously, or subcutaneous), rectum is (for example, by suppository or washing lotion), transdermal (for example, skin electroporation) or by sucking (for example, by aerosol), and, comprise tablet and suspensoid with solid, liquid or gas dosage form.Administration can optionally be carried out with the single unitary dose of continuous treatment or with the single dose treatment.Therapeutic composition can also be oil-emulsion or the dispersion agent form that is combined with lipotropy salt such as pamoic acid, or is used for the biodegradable sustained-release composition form of subcutaneous or intramuscular administration.
Thus, the available pharmaceutical carrier that is used to prepare composition can be solid, liquid or gas; Therefore, the form that can take of composition has preparation (as be combined on the ion exchange resin or be encapsulated in lipid-albumen vesicle), extended release preparation, solution, suspensoid, elixir, aerosol of tablet, pill, capsule, suppository, pulvis, casing or other protection etc.Carrier can be selected from various oil, comprises those following oil: oil, animal, plant or synthetic source, for example peanut oil, soya-bean oil, mineral oil, sesame wet goods.Water, salt solution, the dextrose aqueous solution and dibasic alcohol are preferred liquid vehicles, particularly (when oozing with blood etc.) solution of being used to inject.For example, the preparation that is used for intravenously administrable comprises the aseptic aqueous solution of one or more activeconstituentss, and it is by the preparation aqueous solution that one or more solid active agents are dissolved in the water, make then this solution aseptic and the preparation.The appropriate drug vehicle comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silicon-dioxide, Magnesium Stearate, sodium stearate, Zerol, sodium-chlor, anhydrous skimming milk, glycerine, propylene glycol, water, ethanol etc.Said composition can be added the salt, buffer reagent of conventional medicated premix such as sanitas, stablizer, moistening or emulsifying agent, adjusting osmotic pressure etc.Appropriate drug carrier and their preparation are described among the Remington ' sPharmaceutical Sciences by E.W.Martin.These compositions under any circumstance all contain the active compound of significant quantity and suitable carrier, are used for optimal dose form to the suitable administration of recipient with preparation.
The dosage of The compounds of this invention depends on a large amount of factors, as mode, patient's age and the body weight of administration, the patient's that treated symptom etc., and the most at last by doctor in charge or animal doctor's decision.This amount as the active compound determined by doctor in charge or animal doctor is called " significant quantity " in this paper and claims.For example, the dosage of The compounds of this invention is typically in about 10 to about 1000mg/ days scope.
Now, the present invention will further describe in the following embodiments, and described embodiment is an illustrative, and does not limit the scope of the invention.
Embodiment
Part i: preferred intermediate
Unless point out in addition in description of test, following reagent is available from the retailer that lists in table.
| Raw material | Supplier |
| 4-acetylaminohydroxyphenylarsonic acid benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The 1-amantadine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The 1-aminoidan | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-amino-1-methyl butyl ether | TCI America，Portland，OR |
| Benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Benzyl amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 4-two benzene sulfonyl chlorides | Fluka Chemical Corp.，Milwaukee，WI |
| 4-normal-butyl-benzene sulfonyl chloride | Maybridge plc，Tintagel，Cornwall， UK |
| 4-tert-butylcyclohexyl amine | TCI America，Portland，OR |
| The 2-chlorobenzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-chloro-benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 3-chloro-benzene sulfonyl chloride | Lancaster Synthesis Ltd.，Lancashire， UK |
| 4-chloro-benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-chloro-benzyl amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Raw material | Supplier |
| 3-chloro-4-fluoro-benzene sulfonyl chloride | Alfa Aesar，Ward Hill，MA |
| 3-chloro-2-methyl-benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-(3-chloro-phenyl-) ethamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Cyclo-hexylamine | Eastman Kodak，Rochester，NY |
| Cyclopentyl amine | Lancaster Synthesis Ltd.，Lancashire， UK |
| Decahydroisoquinolinpreparation | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Trans-Decahydroisoquinolinpreparation | TCI America，Portland，OR |
| Decahydroquinoline | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Decahydroquinoline | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The 2,4 dichloro benzene SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2,4-two chloro-benzene sulfonyl chlorides | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride | Advanced ChemTech，Louisville，KY |
| N, the N-dimethyl aminopyridine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 4-fluoro-benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 1-(4-fluorophenyl) ethamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-(2-fluorophenyl) ethamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Raw material | Supplier |
| 2-(4-fluorophenyl) ethamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Hexamethylene imine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Hexamethylene imine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The I-hydroxybenzotriazole hydrate | Acros Organics USA，Morris Plains， NJ |
| The 4-hydroxy piperidine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The 4-hydroxy-piperdine | Fluka Chemical Corp.，Milwaukee，WI |
| Isobutylcarbylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Isobutylcarbylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Isobutylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Isopropylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 4-sec.-propyl-benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| One hydronium(ion) oxidation lithium | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 4-methoxyl group-benzene sulfonyl chloride | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-methoxyl group-benzyl amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-(methoxycarbonyl)-benzene sulfonyl chloride | Alfa Aesar，Ward Hill，MA |
| 2-(2-p-methoxy-phenyl) ethamine | TCI America，Portland，OR |
| Raw material | Supplier |
| The 3-METHOXY PROPYL AMINE | Lancaster Synthesis Ltd.，Lancashire， UK |
| Methylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-methyl-benzyl amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Dl-α-Jia Jibianji amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The 4-methyl piperidine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 4-methyl-piperidines | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Morpholine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-(4-morpholino)-ethamine | TCI America，Portland，OR |
| 1-naphthalene methylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-naphthyl SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The nipecotic acid ethyl ester | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Phenylethylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-phenyl-propyl group amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 3-phenyl-propyl group amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| The 8-quinoline sulfuryl chloride | Lancaster Synthesis Ltd.，Lancashire， UK |
| Raw material | Supplier |
| 1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Thiophene-2-SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Thiophene-2-SULPHURYL CHLORIDE | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| Triethylamine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
| 2-(trifluoromethyl)-benzyl amine | Aldrich Chemical Company，Inc.， Milwaukee，WI |
Intermediate A 1:(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid
Step 1:(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid, ethyl ester
Under argon gas, (0.25mL 1.8mmol) joins (R)-(+)-nipecotic acid ethyl ester (available from Aldrich Chemical Company, Inc., Milwaukee, WI with chlorobenzene sulfonyl chloride; 250mg, 1.6mmol) and triethylamine (0.5mL is 3.6mmol) in the solution in methylene dichloride (5mL).Add another part methylene dichloride (10mL), and with solution in stirring at room 5 days.Reaction mixture is washed with water, and with the water layer dichloromethane extraction.The organic layer that merges is washed with 80% saturated brine, and dry (sal epsom) filters and evaporation, obtains (3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid, ethyl ester (561mg), for colourless viscous oil, it is directly used in next step.NMR shows that needed product exists with a spot of methylene dichloride.
Step 2:(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid
1M lithium hydroxide aqueous solution (3.5mL) is joined (3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid, ethyl ester (from step 1; 560mg) in the solution in tetrahydrofuran (THF) (10mL).In stirred overnight at room temperature, evaporating solvent with the residuum dilute with water, and is acidified to pH1 with solution with reaction mixture.Solution with ethyl acetate extraction 3 times, and wash the organic layer that merges with 80% saturated brine, dry (sal epsom), filtration and evaporating obtains (3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (450mg, 92%), is colourless semisolid.
Intermediate A 2:(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid is (available from Aldrich Chemical Company, Inc., Milwaukee, WI by 2-chlorobenzene sulfonyl chloride and (S)-(+)-nipecotic acid ethyl ester; 166mg 1.1mmol), is used to prepare intermediate A 1 described program preparation.
Intermediate A 3:(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid
(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid is by 2-chlorobenzene sulfonyl chloride and (rac)-nipecotic acid ethyl ester, is used to prepare that intermediate A 1 described program prepares.
Intermediate A 4:(3R)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid
(3R)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid is (available from Aldrich Chemical Company by 4-chlorobenzene sulfonyl chloride and (R)-(+)-nipecotic acid ethyl ester; Inc.; Milwaukee WI), is used to prepare intermediate A l described program preparation.
Intermediate A 5:(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid
(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid is (available from Aldrich Chemical Company by 2,4 dichloro benzene SULPHURYL CHLORIDE and (S)-(-)-nipecotic acid ethyl ester; Inc.; Milwaukee WI), is used to prepare intermediate A 1 described program preparation.
Intermediate A 6:(3S)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid
(3S)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid is (available from Aldrich Chemical Company by 4-chlorobenzene sulfonyl chloride and (S)-(-)-nipecotic acid ethyl ester; Inc.; Milwaukee WI), is used to prepare intermediate A 1 described program preparation.
Intermediate A 7:(3R)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid
(3R)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid is (available from Aldrich Chemical Company, Inc., Milwaukee, WI by thiophene-2-SULPHURYL CHLORIDE and (R)-(+)-nipecotic acid ethyl ester; 166mg 1.1mmol), is used to prepare intermediate A 1 described program preparation, and following change is wherein arranged.With joining in the reaction mixture of second equivalent, because determine SULPHURYL CHLORIDE hydrolysis by NMR from the thiophene-2-SULPHURYL CHLORIDE of different bottles and the triethylamine of second equivalent.
Intermediate A 8:(3S)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid
(3S)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid is (available from Aldrich Chemical Company, Inc., Milwaukee, WI by thiophene-2-SULPHURYL CHLORIDE and (S)-(+)-nipecotic acid ethyl ester; 166mg 1.1mmol), is used to prepare intermediate A 1 described program preparation, and following change is wherein arranged.With joining in the reaction mixture of second equivalent, because determine SULPHURYL CHLORIDE hydrolysis by NMR from the thiophene-2-SULPHURYL CHLORIDE of different bottles and the triethylamine of second equivalent.
Intermediate B 1:2-methyl-cyclopentyl amine hydrochlorate
Step 1.2-methylcyclopentanone oxime
With the 2-methyl-cyclopentanone (11mL, 100mmol), hydroxy amine hydrochloric acid salt (17.76g, 250mmol), and triethylamine (42.5mL, 300mmol) vlil in ethanol (150mL) is spent the night.Evaporating solvent, and with the residuum dilute with water, and be acidified to pH 1.With mixture ethyl acetate extraction 3 times, and with the organic layer water and the salt water washing that merge, dry (sal epsom) filters and evaporation, obtains 2-methylcyclopentanone oxime (10g, 88%), is light yellow oil.
Step 2.2-methyl-cyclopentyl amine hydrochlorate
By Acetyl Chloride 98Min. (2mL) is joined in the ethanol (100mL) in 5 ℃, remove cooling bath then, and make solution prepare the ethanolic soln of HCl in stirring at room 1h.The 2-methylcyclopentanone oxime (from step 1,550mg) is carried palladium (two full toolsettings) with 10% carbon and joins in this solution.Mixture hydrogenation is under atmospheric pressure spent the night, filter then and pass through diatomite.Diatomite is washed well with ethanol, and under vacuum, remove and desolvate.Recrystallization from ethyl acetate obtains 2-methyl-cyclopentyl amine hydrochlorate, is brown solid (330mg, 50%).
Part ii: the preparation of preferred compound
Embodiment 1:(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides
(0.12mL 1.0mmol) joins (3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 1 with isobutylcarbylamine; 248mg, 0.8mmol), the I-hydroxybenzotriazole hydrate (146mg, 1.1mmol), N, N-dimethyl aminopyridine (202mg, 1.7mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (205mg is 1.1mmol) in the solution in methylene dichloride (10mL).Solution in stirring at room 5 days, then with the methylene dichloride dilution, with 1M HCl (20mL), is used salt solution (30mL) washing then, and dry (sal epsom) filters and evaporation.Crude product by using Isco Sg100c RS-40 post, with 15-50% ethyl acetate/hexane wash-out and purifying obtains (3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides (192mg, 64%), is white solid.Mass spectrum (ES) MH+=373.
Embodiment 2:(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides
(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides is by (3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and isobutylcarbylamine, is used to prepare embodiment 1 described program preparation.White solid.Yield: 74%.Mass spectrum (ES) MH+=373.
Embodiment 3:(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4-hydroxy-piperdine-1-yl)-ketone
(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides is by (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 3) and 4-hydroxy piperidine, is used to prepare embodiment 1 described program preparation.White solid.Yield: 67%.Mass spectrum (ES) MH+=387.
Embodiment 4:(3R)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide
(3R)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide is by (3R)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (intermediate A 7) and cyclopentyl amine, is used to prepare embodiment 1 described program preparation.Pale solid.Yield: 73%.Mass spectrum (ES) MH+=343.
Embodiment 5:(3S)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide
(3S)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide is by (3S)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (intermediate A 8) and cyclopentyl amine, is used to prepare embodiment 1 described program preparation.Pale solid.Yield: 73%.Mass spectrum (ES) MH+=343.
Embodiment 6:(3R)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide
(3R)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide is by (3R)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 4) and cyclopentyl amine, is used to prepare embodiment 1 described program preparation.White solid.Yield: 80%.Mass spectrum (ES) MH+=371.
Embodiment 7:(3S)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide
(3S)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide is by (3S)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 4) and cyclopentyl amine, is used to prepare embodiment 1 described program preparation.White solid.Yield: 69%.Mass spectrum (ES) MH+=371.
Embodiment 8:(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-1-yl)-ketone
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-1-yl)-ketone is by (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 3) and octahydro quinoline, is used to prepare embodiment 1 described program preparation.White solid.Yield: 87%.Mass spectrum (ES) MH+=425.
Embodiment 9:(rac)-azepan-1-base-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone
(rac)-azepan-1-base-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone be by
(rac)-and 1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 3) and hexamethylene imine, be used to prepare embodiment 1 described program preparation.White solid.Yield: 65%.Mass spectrum (ES) MH+=385.
Embodiment 10:(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4-methyl-piperidines-1-yl)-ketone
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4-methyl-piperidines-1-yl)-ketone is by (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 3) and 4-methyl piperidine, is used to prepare embodiment 1 described program preparation.White solid.Yield: 77%.Mass spectrum (ES) MH+=385.
Embodiment 11:(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4,4-dimethyl-piperidines-1-yl)-ketone
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4,4-dimethyl-piperidines-1-yl)-ketone is by (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 3) and 4, the 4-lupetidine (is that 3-dimethyl-glutarimide prepares by usefulness lithium aluminium hydride reduction 3; Referring to, D.Hoch and P.Karrer Helv.Chim.Acta 1954,37,397), be used to prepare embodiment 1 described program preparation.White solid.Yield: 82%.Mass spectrum (ES) MH+=399.
Embodiment 12:(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopentyl amide
(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopentyl amide is by (3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid (intermediate A 5) and cyclopentyl amine, is used to prepare embodiment 1 described program preparation.White solid.Yield: 60%.Mass spectrum (ES) MH+=405.
Embodiment 13:(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid diamantane-1-base acid amides
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid diamantane-1-base acid amides is by (3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and 1-amantadine, is used to prepare that embodiment 1 described program prepares.White solid.Yield: 86%.Mass spectrum (ES) MH+=437.
Embodiment 14:(3S)-(7-aza-bicyclo [2.2.1] heptan-7-yl)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone
(3S)-(7-aza-bicyclo [2.2.1] heptan-7-yl)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone is by (3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and 7-aza-bicyclo [2.2.1] heptane hydrochloride (Tyger Scientific Inc.; Ewing; NJ), be used to prepare embodiment 1 described program preparation.White solid.Yield: 76%.Mass spectrum (ES) MH+=383.
Embodiment 15:(3S)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone
(3S)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone is by (3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and octahydro isoquinoline 99.9, is used to prepare embodiment 1 described program preparation.White solid.Yield: 84%.Mass spectrum (ES) MH+=425.
Embodiment 16:(3S)-(4aR, 8aS)-rel-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone
(3S)-(4aR; 8aS)-rel-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone is by (3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and racemize-trans-octahydro isoquinoline 99.9 (TCI America; Portland; OR), be used to prepare embodiment 1 described program preparation.White solid.Yield: 90%.Mass spectrum (ES) MH+=425.
Embodiment 17:(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-morpholine-4-base-ketone
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-morpholine-4-base-ketone is by (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and morpholine, is used to prepare embodiment 1 described program preparation.White foam.Yield: 56%.Mass spectrum (ES) MH+=373.
Embodiment 18:(3S)-([1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-[(cis)-1,3,3a, 4,7,7a-six hydrogen-isoindole-2-yl]-ketone
(3S)-([1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-[(cis)-1,3,3a; 4,7,7a-six hydrogen-isoindole-2-yl]-ketone is by (3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and cis-2; 3,3a, 4; 7; 7a-six hydrogen-1H-isoindole (are by in R.D.Otzenberger etc., J.Org.Chem.1974,39; the preparation of program described in 319), be used to prepare that embodiment 1 described program prepares.Faint yellow semisolid.Yield: 41%.Mass spectrum (ES) MH+=409.
Embodiment 19:(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-methyl-cyclopentyl)-acid amides
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-methyl-cyclopentyl)-acid amides be by
(3S)-and 1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 2) and 2-methyl-cyclopentyl amine hydrochlorate (intermediate B 1), be used to prepare embodiment 1 described program preparation.The pale solid.Yield: 35%.Mass spectrum (ES) MH+=385.
Embodiment 20 to 201: use solid phase synthesis to prepare compound of the present invention
Universal program
Step 1: amine loads on the FMPB resin
With FMPB resin (Calbiochem-NovaBiochem Corp., San Diego, CA; 4-(4-formyl radical-3-methoxyl group phenoxy group) butyryl radicals AM resin, 50-100 order, load 0.98mmol/g) load to IRORI MiniKans (Discovery Partners International, San Diego, CA; 85mg resin/jar) in.To in a reaction vessel, combine with the MiniKans of identical amine reaction, and be suspended in 1, in the mixture of 2-ethylene dichloride, triacetyl oxygen base sodium borohydride (7eq.) and the amine (7eq.) that suits, and it is spent the night in room temperature reaction.After reaction soln is discharged from each reaction vessel, with MiniKans with methanol wash twice, and with 10% (v/v) triethylamine/washed with dichloromethane 1 time.In this stage, will from differential responses container (that is, with the reaction of different amine) all MiniKans combine, and use DMF in succession (1 time), methyl alcohol (1 time) and methylene dichloride (1 time) wash, use DMF (twice) then, methyl alcohol (twice) and methylene dichloride (twice) washing.With MiniKans dried overnight under vacuum.
Step 2: the amine of resin-bonded and the coupling of Fmoc-3-piperidine carboxylic acid
To be suspended in 50/50 mixture of methylene dichloride and DMF from the rapid MiniKans of previous step, add N-Fmoc nipecotic acid (Chem-Impex International, Inc., WOodDale, IL then; 7eq.), bromine three (pyrrolidyl) is Phosphonium hexafluorophosphate (PyBroP (pyrrolydino); Calbiochem-NovaBiochem Corp., San Diego, CA; 7eq.) or O-benzotriazole-N, N, N ', N '-tetramethyl--urea-hexafluoro-phosphoric acid salt (HBTU; Alfa Aesar, Ward Hill, MA; 7eq.) and diisopropylethylamine (7eq.) in.To react on room temperature spends the night.After reaction soln is discharged from reaction vessel, MiniKans is washed and drying as mentioned above.
Step 3: end-blocking program
MiniKans is suspended in the DMF solution of diacetyl oxide (3eq.) and diisopropylethylamine (6eq.), and makes it in room temperature reaction 2 hours.After 2 hours, end-blocking solution is discharged, and MiniKans is washed and drying as mentioned above.
The removal of step 4:Fmoc blocking group
MiniKans is suspended in 20% (v/v) piperidines/DMF solution, and makes it in room temperature reaction 2 hours.After 2 hours, reaction soln is discharged, and MiniKans is washed and drying as mentioned above.
Step 5: sulfonylation
MiniKans is classified on the IRORI sorter, to be used for sulfonylation.To in a reaction vessel, combine with the MiniKans of identical SULPHURYL CHLORIDE reaction, and be suspended in the methylene dichloride.Then, add suitable SULPHURYL CHLORIDE (7eq.) and diisopropylethylamine (7eq.), and make and be reflected at room temperature and spend the night.After reaction soln is discharged from each reaction vessel, MiniKans is washed in each single reaction vessel with methylene dichloride.In this stage, will from differential responses container (that is, with the reaction of different SULPHURYL CHLORIDE) all MiniKans combine and washing as mentioned above.Then, with MiniKans dried overnight under vacuum.
Step 6: the dissociating of product and solid carrier
MiniKans is classified on the IRORI sorter, dissociate being used to.End product and solid carrier dissociating on IRORI dissociates workstation is as follows: with the TFA/ methylene dichloride (50/50, v/v; 3mL) be added in each hole.After 3 hours, solution is discharged and collect, and each hole that will contain MiniKan was with methylene dichloride (3mL) rinsing 20 minutes.With rinsing liquid with merge from the solution of dissociation steps, and the solution that merges is evaporated to drying on Genevac.By the LC-MS assay products.Following purifying purity is lower than 85% compound.
The description of HT purifying
Sample dissolution in the mixture of methyl alcohol, ACN and DMSO, and is used following instrument purifying: Sciex 150EX Mass Spec, Gilson 215 collectors, Shimadzu prep HPLC system, Leap automatic injector.All compounds are used TFA damping fluid LC/MS, purifying in positively charged ion detects: solvent (A) 0.05%TFA/H2O (B) 0.035%TFA/ACN, use suitable linear gradient pattern, 10 minutes, adopt the C-18 post, 2.0 * 10cm, with the 20ml/min wash-out, and the quality guiding is collected.
By solid phase synthesis, amine and SULPHURYL CHLORIDE shown in use is following prepare following compounds:
Embodiment 202:(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3,5,7-trimethylammonium-diamantane-1-yl)-acid amides
With 3,5,7-trimethylammonium-1-amantadine (it is according at J.G.Henkel and J.T.Hane J.Med.Chem.1982,25, the program preparation described in the 51-56) (about 1.0equiv) joins (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 1; About 0.8equiv), I-hydroxybenzotriazole hydrate (1.1equiv), N, in the solution of N-dimethyl aminopyridine (about 1.7equiv) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (about 1.1equiv) in methylene dichloride (about 10mL/ equivalent).With this solution stirring 24h, with the methylene dichloride dilution,, use the salt water washing then then with 1M HCl washing, dry (sal epsom) filters and evaporation.Crude product obtains (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3,5,7-trimethylammonium-diamantane-1-yl)-acid amides by the column chromatography purifying that uses the ethyl acetate/hexane wash-out.
Embodiment 203:(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-hydroxyl-diamantane-1-yl)-acid amides
With amino-1-adamantanol (Aldrich Chemical Company, Inc., Milwaukee, WI) (about 1.0equiv) joins (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (intermediate A 1; About 0.8equiv), I-hydroxybenzotriazole hydrate (1.1equiv), N, N-dimethyl aminopyridine (about 1.7equiv) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (about 1.1equiv) is in the solution of methylene dichloride (about 10mL/ equivalent).With this solution stirring 24h, with the methylene dichloride dilution,, use the salt water washing then then with 1M HCl washing, dry (sal epsom) filters and evaporation.Crude product obtains (rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-hydroxyl-diamantane-1-yl)-acid amides by the column chromatography purifying that uses the ethyl acetate/hexane wash-out.
Embodiment 204: the in vitro tests of The compounds of this invention
By the vitro inhibition of following evidence The compounds of this invention to 11 β-HSD1.
The people HSD1 of purifying is diluted in 50mM Tris-HCl, 100mM NaCl, 0.1mg/mlBSA, 0.02% Lubrol, 20mM MgCl2,10mM glucose 6-phosphoric acid, 0.4mMNADPH, the 60U/ml glucose 6-phosphate dehydrogenase concentration to 1.5ug/ml (enzyme solution).Cortisone (100uM) in DMSO is used 50mM Tris-HCl, and 100mM NaCl (substrate solution) is diluted to 1uM.3 times of the serial dilutions in DMSO of test compound (40uM) that will be in DMSO, and further 20 times of dilutions in substrate solution.Enzyme solution (10ul/ hole) is joined in the 384 hole microtiter plates, then add the compound solution (10ul/ hole) of dilution, and mix aperture.Then, with sample at 37 ℃ of incubation 30min.Be added in 28mM EDTA then, 100nM vitamin H-hydrocortisone, 50mM Tris-HCl, EDTA/ vitamin H-hydrocortisone solution (10ul/ hole) among the 100mM NaCl, the anti-hydrocortisone antibody (3.2ug/ml) in 50mM Tris-HCl, 100mM NaCl, 0.1mg/ml BSA that then adds the 5ul/ hole, and with solution in 37 ℃ of incubation 30min.Add the 5ul/ hole at 50mM Tris-HCl, 100mM NaCl, anti-mouse IgG of the Eu-conjugated among the 0.1mg/ml BSA (16nM) and APC-conjugated streptavidin (160nM), and with solution in room temperature incubation 2 hours.By differentiating fluorescence last readout time at Victor 5 readers (Wallac), and signal is quantitative.
Through type suppresses %=100*[1-(Fs-Fb)/(Ft-Fb)] calculate reagent under various concentration to the active inhibition percentage of HSD1, wherein:
Fs is the fluorescent signal that comprises the sample of reagent,
Fb is at HSD1 and the reagent fluorescent signal in the presence of not,
Ft is in the presence of the HSD1 but do not have fluorescent signal under the situation of reagent.
By IC
50, or obtain the 50 inhibition activity that suppress the compound concentration confirmed test compound of %.The IC that preferred The compounds of this invention demonstrates
50Value is lower than 15 μ M, more preferably between 10 μ M and 1nM, more preferably between 1 μ M and 1nM.
The results are shown in the following table by the vitro inhibition of representative compounds of the present invention 11 β-HSD1:
| Compound | hHSD1IC 50(μM) |
| Embodiment 2 | 0.29 |
| Embodiment 43 | 0.025 |
| Embodiment 50 | 0.031 |
| Embodiment 73 | 0.047 |
| Embodiment 80 | 12 |
| Embodiment 128 | 3 |
| Embodiment 135 | 0.39 |
| Embodiment 157 | 0.91 |
| Embodiment 169 | 0.39 |
| Embodiment 173 | 0.94 |
| Embodiment 175 | 3 |
| Embodiment 187 | 0.19 |
Embodiment 205: the in vivo test of The compounds of this invention
By suppressing in the following body of evidence The compounds of this invention to 11 β-HSD1.
The compounds of this invention is formulated in 7.5% modified gelatin in the water, and IP is delivered medicine to mouse (male C57B1/6J, age～97 day) with 100mg/kg.After 30 minutes, be formulated in the gelatin can plate by administration with the s.c. of 1mg/kg injection.After 40 minutes, from mouse, get blood sample again, and use LC-MS to analyze cortisone, hydrocortisone and drug concentrations.
Calculate inhibitor to the active inhibition percentage of HSD1 by following formula:
Suppress %=100*[1-(C
Inh/ C
Veh)]
Wherein:
C
VehFor cortisone when taking medicine to animal with carrier to the transformation efficiency of hydrocortisone, and
C
InhFor cortisone when taking medicine to animal with inhibitor to the transformation efficiency of hydrocortisone, wherein transformation efficiency C is by formula C=[hydrocortisone]/([hydrocortisone]+[cortisone]) provide.
The variant of particular should be appreciated that to the invention is not restricted to the above-mentioned particular of the present invention, because can obtained and still fall within the scope of appended claim.
Embodiment A
The film coating tablet that can contain following composition with the usual manner manufacturing:
Composition
Every
Nuclear:
Formula (I) compound 10.0mg 200.0mg
Microcrystalline Cellulose 23.5mg 43.5mg
Lactose hydrate 60.0mg 70.0mg
Polyvinylpyrrolidone K30 12.5mg 15.0mg
Primojel 12.5mg 17.0mg
Magnesium Stearate 1.5mg 4.5mg
(nuclear is heavy) 120.0mg 350.0mg
Film coating:
Vltra tears 3.5mg 7.0mg
Polyethylene glycol 6000 0.8mg 1.6mg
Talcum 1.3mg 2.6mg
Ferric oxide (Iron oxyde) (Huang) 0.8mg 1.6mg
Titanium dioxide (Titan dioxide) 0.8mg 1.6mg
Activeconstituents is sieved also and the Microcrystalline Cellulose mixing, use the polyvinylpyrrolidone aqueous solution mixture pelleting.Particle is mixed with primojel and Magnesium Stearate and compress, obtain weighing respectively 120 or the nuclear of 350mg.Should examine with above-mentioned film-coated aqueous solution/suspension and apply.
Embodiment B
The capsule that can contain following composition with the usual manner manufacturing:
Composition
Each capsule
Formula (I) compound 25.0mg
Lactose 150.0mg
W-Gum 20.0mg
Talcum 5.0mg
Described component is sieved and mix, in No. 2 capsules of packing into then.
Embodiment C
Injection liquid can have following composition:
Formula (I) compound 3.0mg
Poly(oxyethylene glycol) 400 150.0mg
Acetate is in right amount to pH5.0
The injection liquid water is supplied 1.0ml
Activeconstituents is dissolved in the mixture of poly(oxyethylene glycol) 400 and water for injection (part).With acetate pH is transferred to 5.0.The water that adds surplus is transferred to 1.0ml with volume.Use suitably this excessive solution, with its filtration, also sterilization in the bottle of packing into.
Embodiment D
The soft gelatin capsule that can contain following composition with the usual manner manufacturing:
Capsule 's content
Formula (I) compound 5.0mg
Yellow wax 8.0mg
Hydrogenated soybean oil 8.0mg
Partially hydrogenated vegetables oil 34.0mg
Soybean oil 110.0mg
Capsule 's content weight 165.0mg
Gelatine capsule
Gelatin 75.0mg
Glycerine 85% 32.0mg
Karion83 8.0mg (dry-matter)
Titanium dioxide 0.4mg
Iron oxide yellow 1.1mg
Activeconstituents is dissolved in the warm molten mass of other composition, mixture is packed in the soft gelatin capsule of suitable size.Soft gelatin capsule after filling is handled according to common program.
Embodiment E
The sachet that can contain following composition with the usual manner manufacturing:
Formula (I) compound 50.0mg
Lactose, fine powder 1015.0mg
Microcrystalline Cellulose (AVICEL PH 102) 1400.0mg
Xylo-Mucine 14.0mg
Polyvinylpyrrolidone K30 10.0mg
Magnesium Stearate 10.0mg
Odor additive 1.0mg
Activeconstituents is mixed with lactose, Microcrystalline Cellulose and Xylo-Mucine, and with the mixed solution of polyvinylpyrrolidone and water with its granulation.Particle is mixed with Magnesium Stearate and odor additive, and in the sachet of packing into.
Claims (50)
1. pharmaceutical composition, it comprises the compound according to formula (I) for the treatment of significant quantity:
Wherein
Q is unsubstituted phenyl,
The phenyl that replaces, its for be independently selected from halogen, low alkyl group ,-COOA ,-CF
3,-OA ,-NC (=O) the group list in A and the phenyl-, two-or trisubstd phenyl,
Unsubstituted heterocyclic, it is 5-or 6-unit heteroaromatic rings, described heteroaromatic rings connects and contains 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The heterocyclic radical that replaces, it is the heterocyclic radical that quilt-COOA or halogen replace,
Naphthyl,
9-and the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, it connects and contains 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The bicyclic heterocyclic radical that replaces, it be 9-or 10-unit bicyclic heterocyclic radical, described bicyclic heterocyclic radical be selected from substituting group list in halogen or the low alkyl group-, two-or three-replacement;
R
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH
2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl
Quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN(A)A，
-DOA；
Or
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional another heteroatoms that is selected among N, O and the S that contains, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement;
A is the low alkyl group that contains 1 to 4 carbon atom,
B is that 3-to 7-unit replaces or unsubstituted carbocyclic ring saturated rings,
D is the bivalent form of A,
E is saturated, the unsaturated or undersaturated heterocycle of part of 5-or 6-unit, and described heterocycle contains 1 to 3 heteroatoms that is selected among S, N and the O,
N is 0 or 1,
Condition is, at R
1Or R
2For H and another are under the situation of low alkyl group, and at Q in contraposition by halogen under the mono-substituted situation, described halogen is a chlorine,
Condition is, at R
1Or R
2For H and another are under the situation of low alkyl group, and at Q in contraposition by low alkyl group under the mono-substituted situation, described low alkyl group contains 1 to 3 carbon atom,
Condition is, at R
1Or R
2For H and another are under the situation of CH2B, and Q be wherein phenyl ring a position by the situation of the mono-substituted substituted-phenyl of halogen under, described halogen is not Cl,
Condition is, at R
1Or R
2For H and another are the phenyl that D-replaces, wherein D is-CH
2CH
2-and phenyl at the ortho position by F under the mono-substituted situation, and Q be wherein phenyl by the situation of the mono-substituted substituted-phenyl of halogen under, the halogen in a position is not Cl,
Condition is, at R
1Or R
2For H and another are-phenyl that D-replaces, wherein D is-CH
2-, and phenyl replaced by the low alkyl group list, and described low alkyl group is at adjacent-CH
3Situation under, and be under the situation of the substituted-phenyl that replaced by halogen of phenyl at Q, be not Cl at the adjacent halogen, or its pharmaceutical salts,
And pharmaceutical carrier.
2. pharmaceutical composition according to claim 1, wherein
Q is unsubstituted phenyl,
The phenyl that replaces, its for be independently selected from halogen, low alkyl group ,-COOA ,-CF3 ,-OA ,-NC (=O) the group list in A and the phenyl-, two-or trisubstd phenyl, and R wherein
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH
2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN (A) A and
-DOA。
3. pharmaceutical composition according to claim 1, wherein
Q is a unsubstituted heterocyclic, and it is 5-or 6-unit heteroaromatic rings, and described heteroaromatic rings connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The heterocyclic radical that replaces, it is the heterocyclic radical that quilt-COOA or halogen replace,
Naphthyl, and wherein
R
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH
2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN (A) A and
-DOA。
4. pharmaceutical composition according to claim 1, wherein
Q is 9-and the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, and it connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The bicyclic heterocyclic radical that replaces, it be 9-or 10-unit bicyclic heterocyclic radical, described bicyclic heterocyclic radical be selected from substituting group list in halogen or the low alkyl group-, two-or three-replacement; Wherein
R
1Or R
2In one be H, and another is selected from:
Low alkyl group,
Mono-substituted or unsubstituted saturated mono-, 5 to 10 yuan of carbocyclic rings of two-or three-ring, wherein mono-substituted carbocyclic ring is replaced by low alkyl group,
Undersaturated 9-of dicyclo part or 10-unit ring,
-CH
2B，
The phenyl that-D-phenyl or D-replace, wherein the phenyl of D-replacement is the D-phenyl, wherein said phenyl quilt-OA, halogen or replacement or unsubstituted low alkyl group list-or two-replace,
-D-naphthyl,
-DE，
-DN (CH
3) the n-phenyl,
-DNC(＝O)A，
-DN (A) A and
-DOA。
5. pharmaceutical composition according to claim 1, wherein
Q is unsubstituted phenyl,
The phenyl that replaces, its for be independently selected from halogen, low alkyl group ,-COOA ,-CF
3,-OA ,-NC (=O) the group list in A and the phenyl-, two-or trisubstd phenyl; And wherein
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional another heteroatoms that is selected among N, O and the S that contains, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement.
6. pharmaceutical composition according to claim 1, wherein
Q is a unsubstituted heterocyclic, and it is 5-or 6-unit heteroaromatic rings, and described heteroaromatic rings connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The heterocyclic radical that replaces, it is the heterocyclic radical that quilt-COOA or halogen replace,
Naphthyl; Wherein
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional contain be selected among N, O and the S in addition-individual heteroatoms, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement.
7. pharmaceutical composition according to claim 1, wherein
Q is 9-and the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, and it connects and contain 1 to 3 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen by ring carbon atom,
The bicyclic heterocyclic radical that replaces, it be 9-or 10-unit bicyclic heterocyclic radical, described bicyclic heterocyclic radical be selected from substituting group list in halogen or the low alkyl group-, two-or three-replacement; Wherein
R
1And R
2The N atom that connects with their forms and replaces or unsubstituted ring Z, and wherein Z is 6-or 7-unit's monocycle or the first dicyclo of 7-to 10-is saturated, part is unsaturated or undersaturated replacement or unsubstituted heterocycle, and described heterocycle contains R
1And R
2The N atom that connects and optional another heteroatoms that is selected among N, O and the S that contains, wherein the heterocycle of Qu Daiing is by low alkyl group or hydroxyl or hydroxyl-alkyl list-or two-replacement.
8. pharmaceutical composition according to claim 1, the described treatment significant quantity of wherein said compound are that about 10mg was to about 1000mg/ days.
9. pharmaceutical composition according to claim 1, wherein halogen is Cl or F.
10. pharmaceutical composition according to claim 1, wherein Q is unsubstituted thiophene, or is encircling quilt-COOCH on the carbon
3Or the heterocyclic radical of Cl list-replacement.
11. pharmaceutical composition according to claim 1, wherein Q is
9-or the unsaturated or undersaturated heterocyclic radical of part of 10-unit's dicyclo, it is by the ring carbon atom connection and have 1 or 2 heterocyclic atom that is selected from sulphur, nitrogen and the oxygen, or
The bicyclic heterocyclic radical that replaces, it is to have one or more substituent 9-or 10-unit bicyclic heterocyclic radicals that are selected from halogen or the low alkyl group.
12. pharmaceutical composition according to claim 11, wherein Q is selected from
13. pharmaceutical composition according to claim 1 is wherein worked as R
1Or R
2In one be H and another be mono-substituted or unsubstituted saturated mono-, two-or during 5 to 10 yuan of carbocyclic rings of three-ring, described saturated carbon ring is 5 or 6 yuan of monocycles or 10 yuan of three ring, and the carbocyclic ring of wherein list-replacement is described by the saturated carbon ring of low alkyl group list-replacement.
14. pharmaceutical composition according to claim 1 is wherein worked as R
1Or R
2In one be H and another during for undersaturated 9-of dicyclo part or 10-unit ring, described ring is
15. pharmaceutical composition according to claim 1 is wherein worked as R
1Or R
2In one to be H and another be-CH
2During B, B is 3-or 6-unit carbocyclic ring saturated rings.
16. pharmaceutical composition according to claim 1 is wherein at R
1Or R
2In the situation of a phenyl that to be H and another replace for-D-phenyl or D-under ,-D-phenyl is-CH
2CH (CH
3)-phenyl ,-CH (CH
3)-phenyl, or-(CH
2) phenyl that replaces of n-phenyl and D-is-CH (CH
3)-(fluoro-phenyl) ,-CH
2CH
2-(fluoro-phenyl) ,-CH
2-(trifluoromethyl-phenyl) ,-CH
2-(methyl-phenyl) ,-(CH
2) p-(chloro-phenyl) ,-(CH
2) p-(methoxyl group-phenyl), or-(CH
2) p-(two-methoxyl group-phenyl),
Wherein n is 1,2 or 3, and
P is 1 or 2.
17. pharmaceutical composition according to claim 1, wherein A is a methyl.
18. pharmaceutical composition according to claim 1 is wherein at R
1Or R
2In one be H and another under the situation of DE, wherein D is-CH
2-or-CH
2CH
2-.
19. pharmaceutical composition according to claim 1, wherein Z is selected from:
20. pharmaceutical composition according to claim 1, wherein Q is by chlorine or methyl substituted phenyl.
21. pharmaceutical composition according to claim 20, wherein Q is by chlorine or methyl substituted phenyl at the ortho position.
22. pharmaceutical composition according to claim 21, wherein Q is mono-substituted.
23. pharmaceutical composition according to claim 22, wherein Q is 2-methyl-phenyl.
24. pharmaceutical composition according to claim 21, wherein Q is a 2-chloro-phenyl.
25. pharmaceutical composition according to claim 21, wherein Q has two or three to be selected from substituent phenyl in chlorine or the methyl.
26. pharmaceutical composition according to claim 25, wherein Q is 2-chloro-6-aminomethyl phenyl or 3-chloro-2-methyl-phenyl.
27. pharmaceutical composition according to claim 1, wherein Q is unsubstituted phenyl.
28. pharmaceutical composition according to claim 1, wherein Q is replacement or unsubstituted thienyl, or replacement or unsubstituted quinolines base.
29. pharmaceutical composition according to claim 28, wherein Q is unsubstituted thiophene-2-base or unsubstituted quinolines-8-base.
30. pharmaceutical composition according to claim 1, the wherein phenyl of Q for being replaced by halogen in the 4-position.
31. pharmaceutical composition according to claim 30, wherein Q is 4-chloro-phenyl or 4-fluoro-phenyl.
32. pharmaceutical composition according to claim 13, wherein R
1Be hydrogen, and R
2Be diamantane-1-base.
33. pharmaceutical composition according to claim 13, wherein R
1Be hydrogen, and R
2Be cycloalkyl.
34. pharmaceutical composition according to claim 19, wherein R
1, R
2The nitrogen that is connected with them is perhydro isoquinoline 99.9-2-base.
35. pharmaceutical composition according to claim 19, wherein R
1, R
2The nitrogen that is connected with them is perhydro quinoline-1-base.
36. pharmaceutical composition according to claim 18, wherein R
1Be hydrogen, and R
2Be 2-(thiophene-2-yl)-ethyl.
37. pharmaceutical composition according to claim 1, wherein said compound is:
R wherein
3For low alkyl group and m are 1,2 or 3.
38. pharmaceutical composition according to claim 1, wherein R
1Be hydrogen, and R
2Be the D-naphthyl.
39. pharmaceutical composition according to claim 1 is wherein at R
1Or R
2In one be H and another under the situation of DE, E is selected from:
40. compound, it is selected from:
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-methyl-cyclopentyl)-acid amides,
(3S)-([1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-[(cis)-1,3,3a, 4,7,7a-six hydrogen-isoindole-2-yl]-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-morpholine-4-base-ketone,
(3S)-(4aR, 8aS)-rel-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone,
(3S)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-2-yl)-ketone,
(3S)-(7-aza-bicyclo [2.2.1] heptan-7-yl)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone,
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid diamantane-1-base acid amides,
(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopentyl amide,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4,4-dimethyl-piperidines-1-yl)-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4-methyl-piperidines-1-yl)-ketone,
(rac)-azepan-1-base-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-1-yl)-ketone,
(3S)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(3R)-1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(3S)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(3R)-1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(4-hydroxy-piperdine-1-yl)-ketone,
(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
2-[3-(2-phenyl-propyl group formamyl)-piperidines-1-alkylsulfonyl]-methyl benzoate,
2-[3-(cyclohexyl methyl-formamyl)-piperidines-1-alkylsulfonyl]-methyl benzoate,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides,
1-(2,4-two chloro-5-methyl-benzenesulfonyls)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-5-trifluoromethyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2-chloro-5-trifluoromethyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2,3-dimethoxy-phenyl)-ethyl]-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-morpholine-4-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(2-chloro-6-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid benzamide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (1-phenyl-ethyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid isobutyl--acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid styroyl-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
2-[3-(2-thiophene-2-base-ethylamino formyl radical)-piperidines-1-alkylsulfonyl]-methyl benzoate,
3-[3-(2-methoxyl group-benzylamino formyl radical)-piperidines-1-alkylsulfonyl]-the thiophene-2-carboxylic acid methyl esters,
3-[3-(2-thiophene-2-base-ethylamino formyl radical)-piperidines-1-alkylsulfonyl]-the thiophene-2-carboxylic acid methyl esters,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid (2-acetylamino-ethyl)-acid amides,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(Toluene-2,4-diisocyanate-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-morpholine-4-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-tetramethyleneimine-1-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-diisopropylaminoethyl-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (pyridin-4-yl methyl)-acid amides; With the mixture of three fluoro-acetate,
1-(3-chloro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(5-chloro-2-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(3-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(3-fluoro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2,3-dimethoxy-phenyl)-ethyl]-acid amides,
1-(3-fluoro-4-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-acetylamino-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-acetylamino-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid (2-morpholine-4-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(4-fluoro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-fluoro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-sec.-propyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(4-methoxyl group-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide; With the mixture of three fluoro-acetate,
1-(4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides; With the mixture of three fluoro-acetate,
1-(4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides; With the mixture of three fluoro-acetate,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid sec.-propyl acid amides,
1-(4-butyl-benzenesulfonyl)-piperidines-3-carboxylic acid methyl acid amides,
1-(5-chloro-3-methyl-benzo [b] thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-methoxyl group-phenyl)-ethyl]-acid amides,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(5-chloro-thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (the 4-tertiary butyl-cyclohexyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid isobutyl--acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid styroyl-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-benzenesulfonyl-piperidines-3-carboxylic acid (1-methoxymethyl-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-benzenesulfonyl-piperidines-3-carboxylic acid 2-methyl-benzamide,
1-benzenesulfonyl-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (3-methoxyl group-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl amide,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclopentyl amide,
1-benzenesulfonyl-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(biphenyl-4-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid [3-(methyl-phenyl-amino)-propyl group]-acid amides; With the mixture of three fluoro-acetate,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [1-(4-fluoro-phenyl)-ethyl]-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2,3-indane-1-base acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (naphthalene-1-ylmethyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-trifluoromethyl-benzamide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-chloro-benzamide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid 2-methoxyl group-benzamide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (the 4-tertiary butyl-cyclohexyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (1-phenyl-ethyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides,
1-(thiophene-2-alkylsulfonyl)-piperidines-3-carboxylic acid styroyl-acid amides,
(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3,5,7-trimethylammonium-diamantane-1-yl)-acid amides and
(rac)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-hydroxyl-diamantane-1-yl)-acid amides, or its pharmaceutical salts.
41. compound, it is selected from:
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl amide,
1-benzenesulfonyl-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-benzenesulfonyl-piperidines-3-carboxylic acid (2-phenyl-propyl group)-acid amides,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
1-(quinoline-8-alkylsulfonyl)-piperidines-3-carboxylic acid cyclohexyl methyl-acid amides,
1-(3-chloro-2-methyl-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopropyl methyl-acid amides,
1-(naphthalene-2-alkylsulfonyl)-piperidines-3-carboxylic acid (3-phenyl-propyl group)-acid amides,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclopentyl amide,
1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid cyclohexyl amide,
(3S)-1-(2,4-two chloro-benzenesulfonyls)-piperidines-3-carboxylic acid cyclopentyl amide,
(rac)-azepan-1-base-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-ketone,
(rac)-[1-(2-chloro-benzenesulfonyl)-piperidines-3-yl]-(octahydro-quinoline-1-yl)-ketone,
(3R)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides and
(3S)-1-(2-chloro-benzenesulfonyl)-piperidines-3-carboxylic acid (3-methyl-butyl)-acid amides, or its pharmaceutical salts.
42. pharmaceutical composition, it comprises according to the compound of claim 40 or 41 and pharmaceutical carrier and/or assistant agent.
43. as therapeutic active substance as any one defined compound in the claim 1 to 41.
44. as therapeutic active substance as any one defined compound in the claim 1 to 41, described therapeutic active substance is used for the treatment of and/or prevent disease by 11beta-Hydroxysteroid dehydrogenase inhibitor adjusting.
45. one kind is used for the treatment of and/or disease that prophylactic treatment is regulated by the 11beta-Hydroxysteroid dehydrogenase inhibitor, be used in particular for the method for the treatment of and/or preventing property treatment type ii diabetes or metabolism syndrome, this method comprises: will be as any one defined compound in the claim 1 to 41 to human or animal's administration.
46. as the application of any one defined compound in the claim 1 to 41 in the disease that the treatment for the treatment of and/or preventing property is regulated by the 11beta-Hydroxysteroid dehydrogenase inhibitor.
47. as any one defined compound application in treating and/or preventing property treatment type ii diabetes or metabolism syndrome in the claim 1 to 41.
48. as any one defined compound in the claim 1 to 41 preparation be used for the treatment of and/or the medicine of the disease that prophylactic treatment is regulated by the 11beta-Hydroxysteroid dehydrogenase inhibitor in application.
49. as any one defined compound in the claim 1 to 41 preparation be used for the treatment of and/or the medicine of prophylactic treatment type ii diabetes or metabolism syndrome in application.
50. aforesaid the present invention.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65827605P | 2005-03-03 | 2005-03-03 | |
| US60/658,276 | 2005-03-03 | ||
| PCT/EP2006/001603 WO2006094633A1 (en) | 2005-03-03 | 2006-02-22 | 1- sulfonyl-pi perdine- 3 -carboxyl i c acid amide derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase for the treatment of type ii diabetes mellitus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101133026A true CN101133026A (en) | 2008-02-27 |
| CN101133026B CN101133026B (en) | 2011-07-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2006800067895A Expired - Fee Related CN101133026B (en) | 2005-03-03 | 2006-02-22 | 1- sulfonyl-pi perdine- 3 -carboxyl i c acid amide derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase for the treatment of type ii diabetes mellitus |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20060199816A1 (en) |
| EP (1) | EP1866285A1 (en) |
| JP (1) | JP2008531616A (en) |
| KR (1) | KR100979577B1 (en) |
| CN (1) | CN101133026B (en) |
| AU (1) | AU2006222372B8 (en) |
| BR (1) | BRPI0609062A2 (en) |
| CA (1) | CA2598610C (en) |
| IL (1) | IL185244A0 (en) |
| MX (1) | MX2007010532A (en) |
| WO (1) | WO2006094633A1 (en) |
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| CN102952059A (en) * | 2011-08-09 | 2013-03-06 | 上海医药集团股份有限公司 | Amide derivative and preparation method thereof, medicine composition and application |
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| WO2006012173A1 (en) * | 2004-06-24 | 2006-02-02 | Incyte Corporation | Amido compounds and their use as pharmaceuticals |
| NZ551603A (en) | 2004-06-24 | 2010-11-26 | Incyte Corp | N-substituted piperidines and their use as pharmaceuticals |
| KR20070050076A (en) * | 2004-08-10 | 2007-05-14 | 인사이트 산 디에고 인코포레이티드 | Amido compounds and their use as pharmaceuticals |
| US8110581B2 (en) * | 2004-11-10 | 2012-02-07 | Incyte Corporation | Lactam compounds and their use as pharmaceuticals |
| CA2585797C (en) * | 2004-11-10 | 2015-01-06 | Incyte Corporation | Lactam compounds and their use as pharmaceuticals |
| US20060122210A1 (en) * | 2004-11-18 | 2006-06-08 | Wenqing Yao | Inhibitors of 11-beta hydroxyl steroid dehydrogenase type I and methods of using the same |
| EP1931652A2 (en) * | 2005-09-21 | 2008-06-18 | Incyte Corporation | Amido compounds and their use as pharmaceuticals |
| JP5475288B2 (en) * | 2005-12-05 | 2014-04-16 | インサイト・コーポレイション | Lactam compound and method using the same |
| WO2007084314A2 (en) * | 2006-01-12 | 2007-07-26 | Incyte Corporation | MODULATORS OF 11-ß HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME |
| BRPI0707408A2 (en) * | 2006-01-31 | 2011-05-03 | Incyte Corp | starch compounds and their use as pharmaceuticals |
| TW200808807A (en) * | 2006-03-02 | 2008-02-16 | Incyte Corp | Modulators of 11-β hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same |
| WO2007103719A2 (en) * | 2006-03-03 | 2007-09-13 | Incyte Corporation | MODULATORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME |
| JP2009535420A (en) * | 2006-05-01 | 2009-10-01 | インサイト・コーポレイション | Tetra-substituted ureas as modulators of 11-beta hydroxyl steroid dehydrogenase type 1 |
| PE20080251A1 (en) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | USES OF DPP IV INHIBITORS |
| JP2009537564A (en) * | 2006-05-17 | 2009-10-29 | インサイト・コーポレイション | Heterocyclic inhibitors of 11-beta hydroxyl steroid dehydrogenase type I and methods using the same |
| WO2007144394A2 (en) * | 2006-06-16 | 2007-12-21 | High Point Pharmaceuticals, Llc. | Pharmaceutical use of substituted piperidine carboxamides |
| EP1918285A1 (en) * | 2006-11-03 | 2008-05-07 | Merck Sante | Diazepane-acetamide derivatives as selective 11beta-HSD1 inhibitors |
| WO2008087654A2 (en) * | 2007-01-16 | 2008-07-24 | Cadila Healthcare Limited | PIPERIDINES AS INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 |
| CL2008001839A1 (en) | 2007-06-21 | 2009-01-16 | Incyte Holdings Corp | Compounds derived from 2,7-diazaspirocycles, inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1; pharmaceutical composition comprising said compounds; Useful to treat obesity, diabetes, glucose intolerance, type II diabetes, among other diseases. |
| CA2711399C (en) | 2008-02-06 | 2016-10-11 | Banyu Pharmaceutical Co., Ltd. | 3-substituted sulfonylpiperidine derivative |
| WO2009100994A1 (en) * | 2008-02-12 | 2009-08-20 | F. Hoffmann-La Roche Ag | Piperidine sulfonamide derivatives |
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| US8258158B2 (en) * | 2009-09-11 | 2012-09-04 | Hoffmann-La Roche Inc. | HSL inhibitors useful in the treatment of diabetes |
| US8513430B2 (en) | 2010-07-27 | 2013-08-20 | High Point Pharmaceuticals, Llc | Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators |
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| GB9604311D0 (en) * | 1996-02-29 | 1996-05-01 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase |
| DE19827640A1 (en) * | 1998-06-20 | 1999-12-23 | Bayer Ag | New imidazotriazine derivatives useful as smooth muscle relaxants for treating e.g. cardiovascular disorders, cerebrovascular disorders, or erectile dysfunction |
| DE19962936A1 (en) * | 1999-12-24 | 2001-06-28 | Bayer Ag | New beta-aminoacid amide derivatives, are integrin antagonists useful for treating inflammatory, autoimmune or immunological disorders e.g. asthma, diabetes or rheumatoid arthritis |
| US20050256159A1 (en) * | 2002-10-11 | 2005-11-17 | Astrazeneca Ab | 1,4-disubstituted piperidine derivatives and their use as 11,betahsd1 inhibitors |
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| WO2004089416A2 (en) * | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Combination of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent |
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| WO2006012173A1 (en) * | 2004-06-24 | 2006-02-02 | Incyte Corporation | Amido compounds and their use as pharmaceuticals |
| WO2006044645A2 (en) * | 2004-10-13 | 2006-04-27 | Adolor Corporation | Sulfamoyl benzamides and methods of their use |
-
2006
- 2006-02-22 CA CA2598610A patent/CA2598610C/en not_active Expired - Fee Related
- 2006-02-22 KR KR1020077019963A patent/KR100979577B1/en not_active IP Right Cessation
- 2006-02-22 CN CN2006800067895A patent/CN101133026B/en not_active Expired - Fee Related
- 2006-02-22 MX MX2007010532A patent/MX2007010532A/en not_active Application Discontinuation
- 2006-02-22 AU AU2006222372A patent/AU2006222372B8/en not_active Ceased
- 2006-02-22 WO PCT/EP2006/001603 patent/WO2006094633A1/en not_active Application Discontinuation
- 2006-02-22 JP JP2007557372A patent/JP2008531616A/en active Pending
- 2006-02-22 BR BRPI0609062-1A patent/BRPI0609062A2/en not_active IP Right Cessation
- 2006-02-22 EP EP06707167A patent/EP1866285A1/en not_active Withdrawn
- 2006-03-01 US US11/365,053 patent/US20060199816A1/en not_active Abandoned
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102952059A (en) * | 2011-08-09 | 2013-03-06 | 上海医药集团股份有限公司 | Amide derivative and preparation method thereof, medicine composition and application |
| CN102952059B (en) * | 2011-08-09 | 2015-03-18 | 上海医药集团股份有限公司 | Amide derivative and preparation method thereof, medicine composition and application |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1866285A1 (en) | 2007-12-19 |
| CA2598610A1 (en) | 2006-09-14 |
| AU2006222372B8 (en) | 2010-04-08 |
| IL185244A0 (en) | 2008-02-09 |
| MX2007010532A (en) | 2007-10-12 |
| BRPI0609062A2 (en) | 2010-02-17 |
| US20060199816A1 (en) | 2006-09-07 |
| AU2006222372A1 (en) | 2006-09-14 |
| JP2008531616A (en) | 2008-08-14 |
| KR20070099680A (en) | 2007-10-09 |
| AU2006222372B2 (en) | 2009-11-19 |
| KR100979577B1 (en) | 2010-09-01 |
| WO2006094633A1 (en) | 2006-09-14 |
| CN101133026B (en) | 2011-07-06 |
| CA2598610C (en) | 2011-05-31 |
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